US 20210077475A1 IN ( 19 ) United States ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2021/0077475 A1 Jacobs et al . ( 43 ) Pub . Date : Mar. 18 , 2021

( 54 ) COMPOSITIONS COMPRISING CYTISINE ( 60 ) Provisional application No. 62 / 899,637 , filed on Sep. IN THE TREATMENT AND / OR 12 , 2019 , provisional application No. 62 / 988,890 , PREVENTION OF ADDICTION IN SUBJECTS filed on Mar. 12 , 2020 . IN NEED THEREOF Publication Classification ( 71 ) Applicants : Achieve Life Sciences , Inc. , Seattle , ( 51 ) Int . Ci . WA ( US ) ; Achieve Pharma UK A61K 31/439 ( 2006.01 ) Limited , Henley - on - Thames ( GB ) A61P 25/34 ( 2006.01 ) ( 72 ) Inventors : Cindy A. Jacobs , Fall City, WA (US ); ( 52 ) U.S. CI . Daniel F. Cain , Vashon, WA ( US ) ; CPC A61K 31/439 ( 2013.01 ) ; A61P 25/34 Anthony Clarke , Checkendon ( GB ) ( 2018.01 ) ( 21 ) Appl. No .: 17 / 101,686 ( 57 ) ABSTRACT Methods of treatment of addiction and /or dependence , meth ( 22 ) Filed : Nov. 23 , 2020 ods of promoting cessation of various addictions , such as smoking and / or vaping, and methods of promoting a reduc Related U.S. Application Data tion in various addictions , such as smoking and / or vaping , ( 62 ) Division of application No. 16 / 993,522 , filed on Aug. uses of cytisine as an addiction cessation treatment, and 14 , 2020 . dosage regimens for the foregoing are provided .

Traditional downward titration Simplified 3 - times daily ( TID ) Day Number Daily Total Dose (mg ) Day Number Daily Total Dose (mg ) of Days Frequency 1.5 mg 30 mg of Days Frequency 1.5 mg 30 mg 1-3 3 6 times 18 1 - 20 20 3 times 4.5 4.12 5 times 7.5 13 - 16 ? 4 4 times 6 17 - 20 4 3 times 21-24 4 2 times 3 6 21-24 4 2 times 3 6 25 1 1 time only 1.5 3 25 1 time only 3 TOTAL 150 mg 300 mg TOTAL 103.5 mg 207 mg Patent Application Publication Mar. 18 , 2021 Sheet 1 of 34 US 2021/0077475 A1

6 3 TotalDose(mg) 103.5mg207 mg13.015FrequencyofDays 3 Simplified3timesdaily(TID) 3times4.5209 2times 1timeonly TOTAL NumberDaily

4 1

Day 1-20 21-24 25 FIG.1

18 12 9 6 3 TotalDose(mg) 150mg300 Frequency1.5mg13.0 4.5 3 7.55times15 6times9 4times6 Traditionaldownwardtitration times3 2times 1timeonly TOTAL NumberDaily ofDays 3 9 4 4 4 1

Day 1-3 4-12 13-16 2017- 2421- 25 Patent Application Publication Mar. 18 , 2021 Sheet 2 of 34 US 2021/0077475 A1

3

7

+3Day FOLLOWUPPHASE 6

202Week5 272)Day( (EndofTreatment)

+1Day PHASETREATMENT ??11 6 FIG.2 312 Day 0Day (Randomization) SCREENINGPHASE

1 87-kea Patent Application Publication Mar. 18 , 2021 Sheet 3 of 34 US 2021/0077475 A1

UP FOLLOW

downwardtitration downwardbitration downwardbitration

TwodosingschedulesTraditionaldownwardtitration&simplified3timesdaily(TID) 15mgoytisinicline 3.0mgoylisinicline 1.5mgqytisinicline 30mgcylisinicline Placebo Placebo FIG.3

= ArmAN-50) ArmB(N=50) ArmC(N=25) ArmD(N=50) ArmE(N-50) ArmF(N=25) 25days Twodose1.5strengthsmg&3.0 RANDOMIZE Duration SCREEN ? Patent Application Publication Mar. 18 , 2021 Sheet 4 of 34 US 2021/0077475 A1

ALL (n=254) 239 (94.1%) (5.9%) 5 8 1 2

PooledPlacebo 48 (94.1%) 3 5.9)(% 2 0 1 0

3.0mg 44 (88.0%) 6 (12%) 1 5 0 0 DownwardTitration 7.8)% 1.5mg (n=51) 47 (92.2%) 1 3 0 0 FIG4.

3.0mg 48 96.0(%) 1 (2.0%) U 0 0 1

1.5mg 98.1%)( 1 (1.9%) 1 0 0

Withdrawbysubject Discontinuedearly AdverseEvent FIULostto Completedtreatmentday25- Reason Patent Application Publication Mar. 18 , 2021 Sheet 5 of 34 US 2021/0077475 A1

25

TritrationDownward1.5mg TritrationDownward3.0mg mgTID1.5 TIDmg3,0 PooledPlacebo 20

. .????????

15

TreatmentDay 5FIG.

X

10

Planned Quit Day 5

0 20 18 16 14 12 10 8 9 2 0 Smoked Cigarettes Patent Application Publication Mar. 18 , 2021 Sheet 6 of 34 US 2021/0077475 A1

TID1.5mg " itrationmgO1.5 titrationmg23 TIDmgN3 Placebo*

??? ?? ? ? ?? ??? ? 1:{ ?{ ????ittt ??? ?? ?? ?? 1010: 3[ tit :1100100161001 571217123137311CALCLEASY: 100 : : 30 :10 :03 33123133 2006[01:10???? ?? ?? ? ? ?? ? ReductioninExpiredCO

FIG.6

( ?????? ??? ?? Kios27001: :2000 Aust:?? t:rit : ????? ?????? ? ????? ??? ?? ??? ARTICCI ???? ? ? ?? ??? Xirtti???? ?? ? .ECC7104 : 313713971113Cross3301)23536373317 AirteitscottyActorytirozine restatustimitrocitetAirteat: cssHirinin :: ? it :;3101033 ?iiii? COROCCO)071310 CECCHIO3133103834731333 citrithet 0101010 Critic 30010AirlCAECACic10: :AD1000473 [10 :1000 900:2000 ReductioninCigarettesSmoked

100% %06 80% %OL 60% 50% 40% 30% 20% 10% %0 Reduction % Patent Application Publication Mar. 18 , 2021 Sheet 7 of 34 US 2021/0077475 A1

titrationmgD1.5 W1.5mgTID titrationmg1.3 TIDmgN3 Placebo2

%8 30% ContinuousAbstinenceWeek(5-8) 16%

27%

22% FIG2.

16%

%54

37671 50% 2017113137303 31:) 3131313131!)2 :13 Anitt):1763917101 34:) 914 ) 1936 10) ?131101 10:) 13110 131231331434C100i 13:01 101111337013737977171373016137015Antic1600!) ! 11 :30 ! 20131113911 ?37633333333 13631313700 52% 4WeekAbstinence

51%

50% 40% 30% 20% 10% 0% Rate Quit Patent Application Publication Mar. 18 , 2021 Sheet 8 of 34 US 2021/0077475 A1

TID O3mg Placebo ContinuousAbstinence (Weeks5-8);p=0.005 Adherencetostudytreatmentwasgreaterthan98.5%acrossallarmsand Cytisiniclinewaswell-toleratedwithnoseriousadverseeventsreported. QuitRatesfor3mgTIDvsPlacebo 8FIG.

4WeekAbstinence: 0.0001

60% 50% 40% 30% 20% 10% 0%

Rate Quit Patent Application Publication Mar. 18 , 2021 Sheet 9 of 34 US 2021/0077475 A1

52

TID37g -PooledPlacebo ---TD1.5mg -Com1.5mg ---Com3mg

-

? r W8 48 49 45

W6 48 47

45 48 Confidenceintervalswith95%SymbolsMeansbyCOVisitare FIG.9 49 50 47 Rand Screen commercialschedule=Cytisine3.0mg Ns TID1.5mg TID3mg Com1.5mg Com3mg Cytisinemgtid=1.5 =Cytisine3.0mgtid 30% 25% 20% 15% 10% 5% 0% PooledPlacebo mgcommercialscheduleCom1.5mg--Cytisine1.5 Monoxide Carbon

Key TID1.5mg TID3mg Com3mg Patent Application Publication Mar. 18 , 2021 Sheet 10 of 34 US 2021/0077475 A1

0PooledPlacebo51 Com1.5mg --TID1.5mg -TID3mg @hoolCom3ingfrom

??? ?? W8 47 49 45 ? wwwww

“nga W4 48 49 47 intervalsConfidenceCotinineVisitwith95%SymbolsMeansbyare FIG.10

TO 49 yo Screen ? schedulecommercialCytisine1.5mg= schedule commercialCytisine3.0mg= Ns TID1.5mg TID3ing Com1.5mg Com3mg Cytisine=1.5mgtid mgtidCytisine3.0= 500% 450% 400% 350% 300% 250% 200% 150% 50% 0% PooledPlacebo Cotinine

Key TID1.5mg TID3mg Com1.5mg Com 3mg Patent Application Publication Mar. 18 , 2021 Sheet 11 of 34 US 2021/0077475 A1

TIDOmg(F)

n=26 w400 0.1289normal)=Homogeneity(PGroup

ComOmg(C) FIG.IIA -25 WWW.X6.64..... Mean Median Quartile px000200 130% 120% 110% 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ) % ( Score Cigs Patent Application Publication Mar. 18 , 2021 Sheet 12 of 34 US 2021/0077475 A1

02 TID3mg(E) :

50n= pocooooooOOOOOOOOO DODOC

TIDOmg(F)

-26n= 0000000000000000 Mean Median Quartile

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% %0 Doo00000000 ) % ( Score Cig Patent Application Publication Mar. 18 , 2021 Sheet 13 of 34 US 2021/0077475 A1

84 Doaro0 12

X

at0Oato# ACHIEVE LIFESCIENCES ? 4weekcontinuousAbstinence OoOOO X

63 atODDOOO# 9

X 56 ogat O30DOO

X X 49 7 0ot Ooooo X X 42 Treatment PostTreatment Continuous4weekAbstinence laawooaa* ? X 35 5 OOOOOOO 12FIG. GracePeriod&weeks X (measured4weeksafterendoftreatment,OFFdrug) (measuredoverlast4weeksontreatment,ONdrug) 4 ?? 282125 X=COconfirmed7daypointprevalenceabstinence(i.e.haveyousmokedtodayorinthelastdays) X

3 Y=COconfirmedendoftreatmentpointprevalenceabstinence(.e.haveyousmokedtoday) X GracePeriod25days 2 Treatment 25days 12weeks 12weeks X ! daDot Cytisiniclineweeks8 } SustainedAbstinenceTimepoints X Treatmentduration Cytisinicline Chantix Chantix Day Chantix ORCA, & Patent Application Publication Mar. 18 , 2021 Sheet 14 of 34 US 2021/0077475 A1

ZI Xiqueu) oqageld %8L

co MESESDESIGN OL

KO

8

9 ??????? EIO1J aguajnaldJuodAed-l % booooooooooo00000000000000odoogooooodoo0o0o0o0o0o0o0oodooo00000oboooooooooooooooodoo0000000000000000oboooooooooooooooodoogooooodbooooo00o0o00ooooooooooooooooooooooooooooooo.. ?UIUISIO Paso de tho

7 4

wowo 0000000000000000000dOooooooooooooooooooooooooooooooooooooooooodo OV OE OZ OL ) % ( Prevalence Point Day - ana1 Patent Application Publication Mar. 18 , 2021 Sheet 15 of 34 US 2021/0077475 A1

15

Weeks4 10 EndofTreatment 4WeeksoffTreatment OR(95%CI) OddsRatios 14.FIG

ko anang D. Cytisinicline Chantix Cytisinicline Chantix Cytisinicline Chantix U ooooo000 Patent Application Publication Mar. 18 , 2021 Sheet 16 of 34 US 2021/0077475 A1

ORCA-1* Meta Analysis** Cochrane 000 20

ng NNNNNNNNNNNNNNNNNNNA 15 Weeks4 EndofTreatment 4WeeksoffTreatment OR(95%CI) OddsRatios FIG.15

oxvxorool 5

0

NRTvsPlacebo PlacebovsZyban ChantixvsPlacebo Cytisinicline Cytisinicline Cytisinicline c00000 Patent Application Publication Mar. 18 , 2021 Sheet 17 of 34 US 2021/0077475 A1

20.00 EstimatedDifference(95%CI) -60.00-40.00-20.000.00

Estimate(95%CI) -23.52-40.15(-6.90,) -9:56(-18.93,-0.19) -1.34(-1771,15.02) -19.96,10.32)-4.82(

StratifierInteractionBetweenArmandBMIEvaluationofPrimaryModel: DifferenceDefinedbyFactorforSubsetsCigaretteScore(%)Analysisof FIG.16 Effect:AmTID3mgminusPooledPlaceboDifference RatioArm (50:51) (16:16) 19:19() (15:16)

Distribution:normalModelCigaretteScore(%)byArmgroupeffect,factorandcovariate.CovarialeScreenMeanCigsid 32 38 31

Value <25 25,30)( Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP NA 0.1303

Factor StratBM Patent Application Publication Mar. 18 , 2021 Sheet 18 of 34 US 2021/0077475 A1

17.14 MedianMean 37.74 26.37 50.0 ScreenMeanCigsid17.34 ScreenMeanCigsld18.00 Variable 50/101(49.5)CigaretteScore%32.53 Parallel:P=0.2754,Difference-9.56

DIN 51/104PooledPlacebo GROUP TIO3mg AmmParallelismofBaseCovariatebyPrimaryModel:Evaluation ScreenMeanCigsld Effect:ArmTID3mgminusPooledPlaceboDifference

10.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 ) % ( Score Cigarette Patent Application Publication Mar. 18 , 2021 Sheet 19 of 34 US 2021/0077475 A1

20.0040.00 EstimatedDifference(95%CI) -80.00-60.0040.00-20.000.00

EstimateC(95% -20.98(-50.21,8.26) -42.11,3.58-19.26() 10DifferenceDefinedforSubsetsbyFactor -12:35(-22.08,-2.63) -4.64(-29.54,20.26) -4.87(-35.84,26.09) -28.37(-57.74,0.99) -10.06(-35,67,15.55) -11.20(-35.13,12.74) -18.85(-63.43,25.73) SourcesPatientEffectAcrossHomogeneityArmof PlaceboStratifiedbyBMIArmTID1.5mgversusPooled RatioArm (52:51) (7:9) (6:5) (6:4) (5:6) (7.7) (12:7) 7:10() (2:3)

103 16 11 11 14 19 17 5 Distribution:nomal.ModelCigaretteScore(%)byArmgroupeffect,factorandcovariatesCovariatesstomiicigsmeano

Value 101 102 103 104 105 106 107 108 Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP NA 0.9336

Factor Site Patent Application Publication Mar. 18 , 2021 Sheet 20 of 34 US 2021/0077475 A1

20.0040.00 EstimatedDifference(95%CI) -60.0040.00-20.000.00

EstimateCI)(95% -29.996-53.52,-6.45) -20.57-43.34,220) -24.261-47,74,-0.79) -9:47(-18.79,-0.15) 8.71(-21.12,38.53) -5.79(-32.54.20.97) 8.30(-20.01,36.62) -32.67,16,12)-8.27( -11.92(-43.47,19.64) PatientSourcesAcrossEffectHomogeneityofArm StratifiedbyBMAmTID3mgversusPooledPlacebo FactorDifferenceSubsetsDefinedbyforCigaretteScore(%)Analysisof ArmRatio 50:51() 9)(3: (6:5) (6:4) (9:6) (8:7) (7:) (5:10)

5 101 12 11 10 14 15 9 Distribution:nomal.ModelCigaretteScore(%)byArmgroupeffect,factorandcovariatesCovariatesstomiicigsmeano

101 102 104 105 106 107 108 Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP NA 0.3422

Site Patent Application Publication Mar. 18 , 2021 Sheet 21 of 34 US 2021/0077475 A1

20.0040.00 EstimatedDifference(95%CI) Shamel It -60.0040.00-20.000.00

Estimate95%CI -19.57-46.52,7.38() -21.950-50.59,6.68) -28.00(-55.04,-0.96) -15.04-38.64,8.57) 74-23.87»14:,-5.60) -6.57(-30.68,17.53) -14.98(-42.61,12.65) 24.626-49,61,0.38-) -2.18(-35.04,30.69)

PatientSourcesAcrossEffectHomogeneityofArm StratifiedbyBMIArCom1.5mgversusPooledPlacebo FactorDifferenceSubsetsDefinedbyforCigaretteScore(%)Analysisof FIG.20 ArmRatio (51:51) 9)(6: (7:5) (9:4) (8:6) 6:10)(

N 102 15 12 13 12 16 9 Distribution:nomal.ModelCigaretteScore(%)byArmgroupeffect,factorandcovariatesCovariatesstomiicigsmeano

Value 101 102 104 105 106 107 108 Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP NA 0.9084

Site Patent Application Publication Mar. 18 , 2021 Sheet 22 of 34 US 2021/0077475 A1

20.0040.00 EstimatedDifference(95%CI) {aningnanah form -80.0060.0040.00-20.000.00

EstimateCI)(95% -31.59(-60.70,-247) -27.83(-54.30,-1.35) -16:51(-25.46,-7.57) -7.06(-29.03,14.92) 11.76-(-37.27,13.75) -20.90(-50.19,8.40) -21.981-47.04,3.09) -8.38(-30.58,13.82) -7.07(-40.34,26.21)

SourcesPatientEffectAcrossHomogeneityArmof PlaceboStratifiedbyBMIAmCom3mgversusPooled FactorDifferenceforSubsetsDefinedbyAnalysisofCigaretteScore(%) FIG.21 RatioArm (50:51) (8:9) (6:4) (4:6) (5:7) (6:7) (7:10) (5:3)

101 17 14 10 10 12 133 17 Distribution:nomal.ModelCigaretteScore(%)byArmgroupeffect,factorandcovariatesCovariatesstomiicigsmeano

Value 101 102 103 104 105 106 107 108 Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP NA 0.8066 Factor Site Patent Application Publication Mar. 18 , 2021 Sheet 23 of 34 US 2021/0077475 A1

10.00100.00

1.00 OR(95%CI) 0.10 0.01

ModelOR(95%CI) 1(<0.01,1) 1.30,14.454.33() 0.22,46.91)3.20( >100{<0.01,) 0.06,28.06)1.25( >100(<0.01,) >100(<0.01,) 1.50(0,07,30.12) <0.01(,)

SourcesAcrossPatientHomogeneityArmEffectof versusPooledPlaceboAmTID1.5mg AnalysisVariable:Cess/W5-8COSuccess,ComparisonArm FIG.22 NA (2:5/18) (3:3/05) (0:6/04) (1:4/15) (2:5/07) (5:7/107) 6/1):9(1 (0:2/12)

ArmNs 52:51() (6:5) (6:4) (5:6) (7:) (12:7) 7:10)( (2:3) Factorinteraction.forArm,andbyanalysisvariablewithtermsLogisticregressionmodelof Value 101 102 104 105 106 107 108

InteractionP 0.9999 Factor Site Patent Application Publication Mar. 18 , 2021 Sheet 24 of 34 US 2021/0077475 A1

10.00100.00

OR(95%CI) ??? 1.00 0.10 0.01

ModelQR(95%CI) 16.00(0.64,>100) 1.51,16.74)5.04( >100(<0.01,-) >100(<0.01,) 0.19,33.40)2.50( >100(<0.01,) >100(<0.01,) 6.00(0.38,95.99) 2.00(0.11,37.33)

SourcesAcrossPatientHomogeneityofAmEffect PooledPlaceboArmTID3mgversus AnalysisVariable:Cess/W5-8COSuccess,ComparisonArm FIG.23 NA (2:1/18) )(1:505 (1:5/04) 6/1:5)(3 (1:7/07) (2:5/07) 3/1:9)(2 (3:3/12)

ArmNs (50:51) (6:5) (9:6) (8:7) (7:) 6:10() (6:3) Factorinteraction.forArm,andbyanalysisvariablewithtermsLogisticregressionmodelof Value 101 102 104 105 106 107 108

InteractionP 0.9913 Factor Site Patent Application Publication Mar. 18 , 2021 Sheet 25 of 34 US 2021/0077475 A1

10.00100.00

1.00 OR(95%CI) 0.10 0.01

ModelOR(95%CI) 3.23(0.94,11.10) 1.60(0.08,33.16) >100(<0.01,-) >100(<0.01,) <0.01(,) >100(<0.01,) >100(<0.01,) 1.80(0.09,36.96) 1.00(0.05,19.73)

SourcesAcrossPatientHomogeneityofArmEffect versusPooledPlaceboArmCom1.5mg AnalysisVariable:Cess/W5-8COSuccess,ComparisonArm FIG.24 NA :8)(15/1 (1:6/05) (2:7/04) )8/1:5(0 (2:2/07) (2:3/07) 5/1):9(1 (2:41)

ArmNs 51:51() (6:9) (7:5) (9.4) (8:6) (4:7) (5:7) (6:10) (6:3) Factorinteraction.forArm,andbyanalysisvariablewithtermsLogisticregressionmodelof Value 101 102 104 105 106 107 108

InteractionP 1,0000 Factor Site Patent Application Publication Mar. 18 , 2021 Sheet 26 of 34 US 2021/0077475 A1

10.00100.00

1.00 OR(95%CI)

be ?} 0.10 0.01

ModelOR(95%CI) 1(<0.01,1) 1(<0.01,1) 1(<0.01,1) 2.24(0.62,8.10) 1.14(0.06,22.82) <0.01(,) >100(<0.01,) 6.75(0.51,89.81) 1.33(0.06,27.79)

SourcesAcrossPatientHomogeneityofArmEffect PooledPlaceboArmCom3mgversus AnalysisVariable:Cess/W5-8COSuccess,ComparisonArm FIG.25 NA 7/1:8)(1 (0:9/05) (0:6/04) (0:4/15) (23/07:) (0:6/07) 4/1:9)(3 (2:31)

ArmNs 50:51() (9:5) (6:4) (4.6) (5:7) (6:7) 7:10)( (5:3) Factorinteraction.forArm,andbyanalysisvariablewithtermsLogisticregressionmodelof Value 101 102 104 105 106 107 108

InteractionP NA 0.9941 Factor Site Patent Application Publication Mar. 18 , 2021 Sheet 27 of 34 US 2021/0077475 A1 110.00

EstimatedDifference(95%CI) -40.0060.0010.00 28 Saunan

-90.00

Estimate(95%CI) -23.52-40.15.-6.90) -9.47(-18.79,-0.15) -10.20(-20.86,0.47) -3.21-26.72,20.30) -15.204-63.85,33.45) 10.48-(-19.98,-0.98) 25.53(-32.83,83.89) -9.53(-22.36,3.30) -9.29(-23.53,4.95) -5.82-19.46,7.81) -13.074-26.73,0.59) -13.49(-30.10.3.13) -6.78-22.77,9.20() -11.05(-2720,6.10) -1.34-17.71,15.02) -4.82-19.96,10.32) -4.86(-18.71,9.00) -14.00(-2779,-0.21) -15.51(-33.62,2.60) -3.264-19.30,12.77) -12.024-28.10.4.05) -21.49(-41.18,-1.81)13.70 (-6.91,34.31) -16.40(-37.06,4.25) -11.99(-30.53,6.56) -12.93(-28.86,3.00) -7.201-18.80,4.39) -14.80(-28.34,-1.27) -4.53(-17.67,8.62)

StratifiedBMIPlacebobyversusPooledArmTID3mg FactorDifferenceSubsetsDefinedbyCigaretteforScore(%)Analysisof FIG.26 AttributesBaselineAcrossEffectArmHomogeneityof (2.2) (1:2) 26:24) 24:27) (16:9) AmRatio (41:39) 7:10() (49:49) 25:31() 25:20() 19:14() (16:18) (15:19) 19:19)( 15:16)( (24:26)26:25 () (15:21) (8:17) (15:10) 11:15() (16:19) 34:32) (23:26) (27:25)

4 56 45 33 34 32 50 25 25 26 49 52 Distribution:norinal.ModelCigaretteScore(%)byArmgroupeffect,factorandcovariatesCovariatesstomiicigsmeano

F 43.0 White Black Other 48.72 <39.63 [39.63,56.611 355.61 30.0< >30.0 (24.0,39.01 <220 22.0,30.01 30.0,43.0(] 17.29< >1729 Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP 0.8379 0.2302 0.9806 0.4684 0.8434 0.1303 0.3734 0.0800 0.2884

ScreenMeanCigs/d(M) Factor SmoketixDur(V)M SmokehixDur(V)O SmokeHixDur(V)Q Race Hispanic Age(M) Age1 StratBMI 2QuitHx Patent Application Publication Mar. 18 , 2021 Sheet 28 of 34 US 2021/0077475 A1

# 100.00 ?mauf ????????? 10.00

***** OR(95%CI)

* }~~~. 0.10 ******** ********** 0.01

0.01,11(<) 12.50(1.39,>100) 9.60(0.78,>100) ModelOR(95%CI) 5.04(1.51,16.74) 6.22(1.60,24.25) <0.01,) )>100<0.01, 4.96(1.49,16.55) 4.39(1.00,19.21) 7.39(0.80,68.03) 12.18(1.37,100) 0.58,12.362.67() 4.64(0.46,46.55) >100(<0.01,) 1.94(0.35,10.66) 5.00(0.48,52.37) 0.66,23.223.92() 7.50(0.74,76.38) 2.70(0.60,12.16) 4.58(0,45,46.98) >100<0.01,100) 0.38,9.851.92() >100(<0.01,) >100(<0.01,) 1.50(0.23,9.61) 2.83(0.43,18.47)7.17 (1.42,36,32)5.90(1.35,25.83) 5.45(0.57,51.84)

StratifiedbyBMIPooledPlaceboArmTID3mgversus AnalysisVariable:Cess/W5-8COSuccess,ComparisonArm FIG.27 AttributesAcrossBaselineEffectHomogeneityofArm (14:27/336)9) (0:7/1 (1:1/02) (15.344:45) (0:1/02) (8:17/328) (5:14/113) (6:10/018) 411/3(:16) (8:16/125) :19/322)7 (5:11/09) 3.5/1:16) (4:11/010) (3:8/312) (10:13/323) (7:18/119) (9:17/123) (6:18/324) 4:12(1:15) (6:13/217) (5:10/115) (5:12/111) (5:10/021) 13/315):5( (4:12/217) (11:23/230) (5:22/124)

ArmNs 50:51() (41:39) 7:10() (2:) (1:2) 25:31() 25:20() 26:24) (24:27) (19:14) (16:18) (15:19) (19:19) (15:16) (24:26) (26:25) 17:12() 18:18)( (16:9) (8:17) 15:10)( (11:15) (34:32) (23:20) (27:25)

F 30.0,43.0(] 43.0 17.29 White Black Other Yes 48.72 <39.63 139.63,55.61155.61 [25,301 30.0< (24.0,39.01 ME 22.0 (22.0,30.01 17.29< termsforArm,FactorandAmbyinteraction.Logisticregressionmodelofanalysisvariablewith InteractionP 0.9996 0.6994 0.2618 0.8327 0.9078 0.2566 0.7072 0.9542

ScreenMeanCigs/d(M) Factor SmokeMixDur(V)M SmokehxDurV)D SmokeHixDur(V)Q Age(M) Age(1 StratBMI Race Hispanic Sex Patent Application Publication Mar. 18 , 2021 Sheet 29 of 34 US 2021/0077475 A1 40.00 20.00 *** ocero EstimatedDifference(95%CI) -20.00 -40.00 -60.00 -80.00

)Estimate95%CI -9.474-18,79,-0.15) -22.021-37.52,-6.51) -12.861-24.10,-1.61) -8.45-20.10,3.20) -9.38-18.88,0.11) 10.944-20.88-,-1.00) -17.33,3.21-7.06() -20.77(-46.03,4.48) -14.02,9.26)-2.38( -6.90(-16.80.2.99) 10.28-(-31.74,11.17) -1.351-18.53,15.84) -12.94-29.43,3.56) -7.19(-17.61,3.23) -16.764-37.29,3.77) -29.84(-69.03,935) -30.07,29.95-0.06() -20.78,3.46-8.66() 11.44-26.94,4.06-)

interventionsHomogeneityofArmEffectAcrossPriorAnti-Smoking StratifiedbyBMIPooledPlaceboversus3mgArmTID DefinedFactorSubsetsbyDifferenceforCigarette(%)AnalysisScoreof FIG.28 RatioArm (50:51) 45:39() 5:12() 32:32)( 18:19() 43:39)( 7:12() 37:33() 19:15)( 31:36)( (39:41) 11:10)( 45:49)( (43:47) (32:30) 18:21()

N 101 21 7 62 Distribution:normalModelCigaretteScore(%)byArmgroupeffect,factorandcovariates.Covariatesstomiicigsmeano Value Yes Yes Yes Yes Yes

Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP 0.3206 0.0508 0.2686 0.6645 0.4143 0.3179 0.7831

KALING ChantixMostRecent ZybanHx RecentMostZyban RecentMostVape NRTMostRecent >2QuitTx Chantix HxVape NRTHx Patent Application Publication Mar. 18 , 2021 Sheet 30 of 34 US 2021/0077475 A1

mungonyangmga 100.00 wwwman . 10.00

? 1.00 OR(95%CI) ?? ingin 0.10 WWW whinyanggung 0.01

ModelOR(95%CI) 5:04(1.51,16.74) 7.52(1.55,36.55) 0.31,35.883.33() 5.00(0.95,26.31) 0.92,31.665.41() 5.20(1.33,20.31) 4.40(0.31,62.66) 6.56(1.31,32.95) 0.53,23.953.56() >100[<0.01,) 3.27(0.88,12.17) 6.72(1.34,33.73) 3.33(0.46,24.06) 5.08(1.50,17.16) >100(<0.01,) 5.19(1.53,17.62)Nina >100(<0.01,) 7.33(1.44.37.42) 2.710.42,17.36() AnalysisVariable:CessW5-8/COSuccess,ComparisonArm HomogeneityofArmEffectAcrossPriorAnti-Smokinginterventions FIG.29 16:13/015) PlaceboArmTID3mgversusPooled (13:32/237) 10)(2:3/2 {8:241230) (7:11/217) (13:30/336) (25/1:10 (11:26/231) (4:91216) (9:22/432) (10:291239) (5:6,28) 31/445):(14 (1:4702) (14:291443) (1:6/04) 21/2:28)(11 (4:14/219)

(50:51) (45:39) (6:12) (32:32) 18:19() (43:39) 7:12() 37:33() (19:15) (31:35) (39:41) (45:49) (5:2) (43:47) (32:30) 18:21()

Value Yes Yes Yes Yes andAmbyFactorinteraction,variablewithtermsforArmLogisticregressionmodelofanalysis

InteractionP 0.5732 0.9488 0.9118 0.6279 0.9733 0.5863 0.9799 0.9817 0.4264

ChantixMostRecent RecentMostZyban RecentMostVape NRTMostRecent >2QuitTx Chantixhx ZybanHx 4xVape NRTHX Patent Application Publication Mar. 18 , 2021 Sheet 31 of 34 US 2021/0077475 A1 40.00 20.00 ***** 0.00 EstimatedDifference(95%CI)

{a* .40.00-20.00 -60.00 -15.204-27.97,-2.43) -23.734-40.37,-7.09) -25.32-45.74,-4.91) -9.47(-18.79,-0.15) -17.85(-31.04,-4.65) 14.17-30.74,2.41) 1.534-1770,20.77) -21.50(-40.72,-2.28) -4.084-17.78,9.63) -8.60(-24.38.7.18) -19.47(-35.91.-3.02) -24.61,9.91-7.35()-22.26 (-40.50,-4.02) -19.401-32.53,-6.28) 0.02-13.21,13.25) -2.96(-16.40,10.47) -5.16-21.97,11.66) -11.76(-28.32,4.81) -7.07(-26.37,12.24) 13.87-33.00,5.27-) -0.886-18.02.16.25) 2.33(-17.15,21.811 -11.96-30.37,6.46) -27.04,5.54-10.75()4.28(-11.86,20.41 ) 14.34-33.46,4.78-) -4.08-23.55,15.39) -15.28,23.043.88(

MarkersAcrossBaselineLabEffectHomogeneityofArm FactorDefinedSubsetsbyDifferenceforCigaretteScore(%)Analysisof 30FIG. StratifiedbyBMIPooledPlaceboArmTID3mgversus 25:22) RatioArm 24:25)( 24:26() 16:16)( 16:18() 16:17)( 12:12() 12:13)( 13:12)( 25:29() 16:15() 19:17() (15:19) (14:11) 14:14() 11:15)( (23:27) 26:24)( (14:19) (17:16) 18:16() (8:17) 15:10() (11:14) 15:10)(

N 49 34 24 25 25 54 31 36 34 28 25 25 25 25 Distribution:normal.ModelCigaretteScore(%)byArmgroupeffect,factorandcovariatesCovariatesstomiicigsmeano

?. 116.0,24.0) 26.0 0.3529 0.4444 10.2832,0.3529)10.3529,0,4865] 0.4865 <16.0 >24.0 <268.0 >268.0 233.0,313,0(] (211.0 >=373.5 0.3529< 10,2984,0.4444 0.2832< 14.0,20.0(20.0,26.01 ( 211.0,268.0 1268.0,373.51 Effectoffocusishomogeneityacrossallsubgroupsdefinedbyfactorvalues. InteractionP 0.1201 0.7352 0.3761 0.3011 0.3368 0.0434 0.0652 0.1957

CarbonMonoxideBase(M) CarbonMonoxideBase(O CarbonMonoxideBase(Q) CotinineBase(M) CotinineBase(0) CotinineBase(Q) Factor NMRBase(M) NMRBase(0) NMRBase(Q) Patent Application Publication Mar. 18 , 2021 Sheet 32 of 34 US 2021/0077475 A1

women 100.00

******** ?????d????? grannar ??????? 10.00

OR(95%CI)

# II ill 0.10

0.01

8:17/319) 7:18/128) 4:15/116) (5:10/019) 8/3):8(3 11)9/0:(5 10/1:13)(4 :10)78/0 5:22/124) (3:14/116) 11/0:13)2 )(4:201223 (1:15/115 (6:10/215 (1:111111 (3:91112) (5:6/113) (6:10/312) )(3:8/015 8/2:17)(6 10/0:16(7(2:16/214 155/2:)(3 (2:13/010) (5:12/017) 11(4:7/3 (6:6/012 (3:11/111) (5:21222)26:24 (23:27)10:13/215 (23:26)10:13/323 ArmNsORNS AnalysisVariable:Cess/CoSuccessWeeks5-8,ComparisonArm EffectModifierAnalysesSecondaryBinaryOutcome (50:51) 24:25)( 24:26)( 16:16)( (16.17) 12:13)( 25:22() (25:29) (16:15) 19:17(] 11:11)( 14:14() 11:15) 14:19)(17:16) 18:16)((8:17) (15:10) 16:17)( 17:17)( (11:14) (12:12) 14:12)( FIG.31 PooledOmgNOTStratifiedArmTID3mg(E)versus (12:12 13:12 (15:19 27:25 117.29,20.1413:13() 16:18()0.2984,0.4444[ 211.0.268.01(15:10)[373.51(11:14)268.0, 17:17)(14.00,19.71 10.3529,0.4865) 17.29 Value <0.2984 0.4444> 0.2832 (0.2832,0.35291 20.4365 <20.0 -20.0 (16.0,24.0) (14.0 114.0,20.0J26.0120.0, >26.0 233.0< 233.0,313.01313.0>= <17.29 (12.86 12.86,17.29 20.14>=

InteractionP 0.2944 0.3829 0.2925 0.3738 0.9732 0.9542 0.9986 0.9965

CarbonMonoxideBase0.3371(M) CarbonMonoxideBase(1)0.9223 CarbonMonoxideBase(Q0.7627) variableanalysiswithtermsforregressionLogisticmodelof ScreenMeenCigs/d(M) ScreenMeenCigsid(0) CotinineBase(M) CotinineBase(1) CotinineBase(Q.) ScreenMeenCigsldU Factor NMRBase(M) NMRBase(1) NMRBase(Q) interaction,ArmbyFactorAmand Patent Application Publication Mar. 18 , 2021 Sheet 33 of 34 US 2021/0077475 A1

6

UnfavorableOutcomes 5

O Reference95%ExactConfidenceintervalforDifference:5.3to33.1 SuccessCess5-8/COAnalysisPointTipping ReferenceEstimate:15/50-475130.0%-7.8=22.2points PooledPlacebo:Assessed#NotmySuccess 3 FIG.32

?

PooledPlacebo:N51,#Success-4NotAssessed=6 2 Assessed=3Success-15,#NotTID3mg:N50 Reference

0 2 0 Success Assessed Not : 3mg TID Patent Application Publication Mar. 18 , 2021 Sheet 34 of 34 US 2021/0077475 A1

1 24 Monthly Follow-up Monthly Follow-up Monthly Follow-up 16

0: 23:07 11313! ???? ?? ? ?? ??ManCit ?? ?? ? :1610?? ?? ? ) ?????? ? ?? ?? ??7307?? ? ?:? ) 31031931 AC01030107€1t: 30Act 1:30:10 1410 : 10 :31 ):101931971 10 192123923:31 )39215391151311133633733031 01:10 : 07160901 100003133132333:0010 :300 :1 9101112 123314033133134139912310331230331332392032313311 titant138933743730:7 MCHCEC07161 € titfitte 33363911 )2011 )1981 11063733 73971231331011 Placebo 6weeks Ctrl starttitare*****)9713170 Placebo weeks6“ tit ;ft.srtis Cytisinioline Weeks6 313011 340) *** Cari: 10 :00 )43391 2018 )331 )19713331971 )531103110 )311036110 13 )3031 )130703070707331033391( 10:10 !31371397133733740 124330331333 )(110110101010131331431371131311231371381391 ( 73111111113710 7 ????? 19710711713137630103370071ACCELECT1371317101313736 4313700307103933331397313745377013738 6 130973715 FIG.33 5 100110003031379citrocitetit}}!) 1110113777333333333 119339 53113171**** HEARLIKE !)+370371372 517331 AGICANET)3372 :31 :3 7 373737:) 1911 19110337001 ( :1 1307603370071)1133037 10:2010 011 : 14 weeks )93133123971 :)3303313? ) 2 6Weeks 6Weeks Placebo )31 :4337403 Cytisinicline Cytisinicline 312 3713131!)? 13111111 )31 :9713 )3533731 39 )717 ) 11 :1973uset :Stist Etift: 33533123133199:113+37130131371219112313313 !103 ."137107131331010376 900333333333 133191131371381197713971231331393133133 233233333333333 Week"T

AmmB AmA 12WeeksNe250 Placebo6Weeks N=-250 Placebo CYT6Weeks BYTUWeeks WeeksQYA6

RANDOMIZATION US 2021/0077475 A1 Mar. 18 , 2021 1

COMPOSITIONS COMPRISING CYTISINE have an improved safety profile , and / or can more success IN THE TREATMENT AND /OR fully treat individuals who have failed to quit nicotine using PREVENTION OF ADDICTION IN SUBJECTS the known treatments . IN NEED THEREOF SUMMARY PRIORITY CLAIM [ 0009 ] In one aspect , provided herein is a method of treating of nicotine addiction in a subject, comprising [ 0001 ] This application is a divisional of U.S. patent administering cytisine in equal dosage amounts two times application Ser. No. 16 / 993,522 , filed on Aug. 14 , 2020 , per day (“ bid ” or “ BID ” ) or three times per day ( “ tid ” or which claims priority to U.S. Provisional Application No. “ TID " ) to a subject in need thereof. 62 / 988,890 filed on Mar. 12 , 2020 and U.S. Provisional [ 0010 ] In another aspect , provided herein is a method of Application No. 62 / 899,637 filed on Sep. 12 , 2019 , the treating nicotine addiction, promoting cessation of smoking , entire contents of each of which are incorporated herein by and / or promoting a reduction in smoking in a subject in need reference and relied upon . thereof, the method comprising administering cytisine pro vided in a unit dose of 3.0 mg or 1.5 mg of cytisine three BACKGROUND times daily to the subject. [ 0002 ] Nicotine is an addictive substance that is rapidly [ 0011 ] In still another aspect , provided herein is a method absorbed during cigarette smoking . The drug distributes of treating nicotine addiction in a subject, comprising quickly and is thought to interact with neuronal nicotinic administering cytisine at a dose of either 1.5 mg or 3.0 mg acetylcholine receptors ( nACHRs) in the central nervous of cytisine three times daily to a subject in need thereof. system ( CNS ) . Nicotine addiction results , at least in part, [ 0012 ] In still another aspect , provided herein is a method from this interaction . Although many smokers attempt to of treating nicotine dependence in a subject, comprising cease smoking , few succeed without pharmacological sup administering cytisine at a dose of either 1.5 mg or 3.0 mg portive treatment. of cytisine three times daily to a subject in need thereof. [ 0003 ] Tobacco smoking contributes to some 7 million [ 0013 ] In still yet another aspect , provided herein is a premature deaths each year worldwide. Smoking is highly method of treating nicotine addiction in a subject, compris addictive, with more than 95 % of unaided attempts at ing administering cytisine to a subject in need thereof, cessation failing to last 6 months . It has been estimated that wherein the subject is a refractory patient who has failed for every year that a person delays stopping smoking beyond treatment with one or more nicotine addiction treatments . his or her mid - 30s , that person loses 3 months of life [ 0014 ] In yet another aspect , provided herein is a method expectancy . The World Health Organization's Framework of preventing smoking relapse in a subject in need thereof, Convention on Tobacco Control identifies evidence - based the method comprising administering cytisine provided in a approaches to promote smoking cessation , which include unit dose of ( a ) two tablets, each tablet either containing 1.5 mass - media campaigns, tax increases on tobacco , and help mg or 3.0 mg of cytisine , ( b ) a single tablet either containing for smokers wanting to stop . 1.5 mg or 3.0 mg of cytisine , or ( c ) three tablets, each tablet [ 0004 ] The pharmacotherapies currently available in the containing 1.0 mg of cytisine , three times daily to the U.S. and Western Europe to help smokers stop include subject. nicotine replacement therapy (NRT ) and two non - nicotine [ 0015 ] In a further aspect , provided herein is a method of containing medications: bupropion ( Zyban® , Glaxo preventing smoking relapse in a subject in need thereof, the SmithKline) and varenicline ( Chantix® /Champix® , Pfizer ). method comprising administering cytisine to the subject, NRT and bupropion appear to have about equal efficacy . wherein the subject is a refractory patient who has failed Varenicline is more effective than single NRT and bupro treatment with one or more smoking cessation treatments pion , although combination NRT is comparable in efficacy. selected from the group consisting of NRT, administration of bupropion , administration of varenicline, electronic ciga [ 0005 ] ( - ) - Cytisine ( cytisinicline; commonly referred to rettes ( e -cigarettes ), and vaping. simply as cytisine ) is a plant - based alkaloid isolated from [ 0016 ] In one embodiment, each of the three daily admin seeds of Cytisus laburnum L. (Golden chain ). References istrations occur morning, noon , and evening, respectively , or herein to cytisine refer to ( - ) -cytisine , cytisinicline. in approximately intervals of 4-5 hours. In one embodiment, [ 0006 ] Cytisine's mechanism of action has assisted basic the administration occurs for a period of at least about 6 pharmacologists in understanding the complex pharmacol weeks, at least about 12 weeks , at least about 24 weeks or ogy of the various subtypes of the nicotinic acetylcholine indefinitely. In another embodiment, the administration receptor. These studies have shown that both nicotine and occurs for a period of at least about 6 weeks or at least about cytisine bind strongly and preferentially to alpha4 , beta2 12 weeks or repeated for 6-12 weeks indefinitely. ( 04B2) receptors that mediate the release of dopamine in the [ 0017 ] In some embodiments, cytisine is provided in a unit shell of the nucleus accumbens and elsewhere . This receptor dose of about 1.0 mg to about 6.0 mg of cytisine one to six subtype has been implicated in the development and main times daily to a subject in need thereof. In some embodi tenance of nicotine dependence and was the primary target ments, cytisine is provided in a unit dose of about 1.0 mg to for the drug varenicline, referred to above. about 6.0 mg of cytisine three to six times daily to a subject [ 0007 ] Tabex® , containing the active substance cytisine , in need thereof. In some embodiments, cytisine is provided has been licensed and marketed in Central and Eastern in a unit dose of 1.5 mg of cytisine three times daily to a Europe for several decades by Sopharma PLC ( Sophia , subject in need thereof. In some embodiments, cytisine is Bulgaria ). provided in a unit dose of 1.5 mg of cytisine six times daily [ 0008 ] A need exists for nicotine addiction treatments with to a subject in need thereof. In some embodiments, cytisine patient - friendly regimens that are less costly, more effective , is provided in a unit dose of 3.0 mg of cytisine three times US 2021/0077475 A1 Mar. 18 , 2021 2 daily to a subject in need thereof. In some embodiments, [ 0030 ] FIG . 8 is a representative graph depicting a com cytisine is provided in a unit dose of 3.0 mg of cytisine six parison between the quit rates between 3.0 mg three times times daily to a subject in need thereof. per day ( TID ) and placebo after a 4 -week abstinence and [ 0018 ] In some embodiments , the cytisine is administered during continuous abstinence ( Weeks 5-8 ) . in one or more unit doses . In some embodiments , each unit [ 0031 ] FIG . 9 is a representative plot depicting the expired dose ( e.g. , a tablet or a capsule) of cytisine comprises 1.0 mg CO levels in parts per million for the pooled placebo, TID of cytisine. In some embodiments, each unit dose ( e.g. , a 1.5 mg , TID , 3.0 mg , commercial dosing titration schedule tablet or a capsule ) of cytisine comprises 1.5 mg of cytisine. ( COM ) with 1.5 mg , and COM with 3.0 mg treatment arms In some embodiments, the unit dose of cytisine comprises at the screening visit , at Week 4 , and at Week 8 in accor 3.0 mg of cytisine. In some embodiments, each unit dose is dance with the present technology. a tablet, for example, a compressed , film coated tablet . [ 0032 ] FIG . 10 is a representative plot depicting the serum [ 0019 ] In some embodiments, the subject is a refractory cotinine levels for the pooled placebo , TID 1.5 mg , TID 3.0 patient who has failed treatment with one or more nicotine mg , COM 1.5 mg , and COM 3.0 mg at the screening visit , addiction treatments . In some embodiments , the subject is a at Week 4 , and at Week 8 in accordance with the present refractory patient who has failed treatment with two or more technology nicotine addiction treatments . In some embodiments, the [ 0033 ] FIGS . 11A - 11B are representative plots depicting a nicotine addiction treatments are selected from NRT, admin comparison between the group homogeneity for the percent istration of bupropion, administration of varenicline, elec age of expected cigarettes smoked ( Cigarette Score ) com tronic cigarettes, vaping, and a combination thereof. pared between COM 0 mg and TID 0 mg , and between TID [ 0020 ] In some embodiments, the subject smoked ten or 0 mg and TID 3.0 mg in accordance with the present more cigarettes per day prior to the administration of technology cytisine. In some embodiments , the subject has expired air [ 0034 ] FIG . 12 is a schematic of the study design for carbon monoxide ( CO ) concentration of about 10 parts per comparing cytisinicline ( cytisine ) and Chantix® in accor million ( ppm ) or greater prior to the administration of dance with the present technology . cytisine. In some embodiments, the subject ( a ) smoked ten [ 0035 ] FIG . 13 is a representative graph depicting the CO or more cigarettes per day prior to the administration of confirmed quit rates between 3.0 mg of cytisinicline and 3.0 cytisine, ( b ) has expired air CO concentration of about 10 mg of Chantix® at 4 weeks and at 12 weeks of treatment in ppm or greater prior to the administration of cytisine , or ( c ) accordance with the present technology . a combination of ( a ) and ( b ). [ 0036 ] FIG . 14 is a representative plot comparing the odds [ 0021 ] In some embodiments , the subject experiences no ratio of cytisinicline and Chantix® at 4 eeks , end of adverse events after receiving the cytisine treatment. In treatment, and 4 weeks off treatment in accordance with the some embodiments, the adverse event is selected from the present technology group consisting of an upper respiratory tract infection [ 0037 ] FIG . 15 is a representative plot comparing the odds (URTI ), abnormal dreams, nausea , insomnia , headache , ratio of cytisinicline at 4 weeks , end of treatment, and 4 fatigue , and constipation . weeks off treatment to current products in accordance with [ 0022 ] In some embodiments, the method further com the present technology. prises providing behavioral support to the subject. [ 0038 ] FIG . 16 is a representative plot depicting the inter action between the 3.0 mg TID arm and the BMI stratifier in BRIEF DESCRIPTION OF THE DRAWINGS accordance with the present technology . [ 0023 ] FIG . 1 is a schematic of dosing schedules accord [ 0039 ] FIG . 17 is a representative plot depicting an assess ing to the study design of Example 1 in accordance with the ment using parallelism between the arms of the straight- line present technology . relationships between the Cigarette Score and the baseline [ 0024 ] FIG . 2 is a schematic of the study design of mean number of cigarettes in accordance with the present Example 1 in accordance with the present technology. technology [ 0025 ] FIG . 3 is a schematic of the dosing strengths, [ 0040 ] FIG . 18 is a representative plot depicting Effect schedules, and duration according to the study design of Modifier Analyses ( EMAS ) for Cigarette Score across clini Example 1 in accordance with the present technology . cal sites for cytisine 1.5 mg TID compared to pooled placebo [ 0026 ] FIG . 4 is a schematic showing the subject popula in accordance with the present technology. tion disposition according to the study of Example 1 in [ 0041 ] FIG . 19 is a representative plot depicting EMAs for accordance with the present technology . Cigarette Score across clinical sites for cytisine 3.0 mg TID [ 0027] FIG . 5 is a representative graph depicting a number compared to pooled placebo in accordance with the present of cigarettes smoked per treatment arm by day of treatment technology. according to the study of Example 1 in accordance with the [ 0042 ] FIG . 20 is a representative plot depicting EMAs for present technology Cigarette Score across clinical sites for cytisine 1.5 mg [ 0028 ] FIG . 6 is a representative graph depicting a reduc COM compared to pooled placebo in accordance with the tion in cigarettes smoked versus expired CO in the subject present technology population of Example 1 in accordance with the present [ 0043 ] FIG . 21 is a representative plot depicting EMAs for technology. Cigarette Score across clinical sites for cytisine 3.0 mg [ 0029 ] FIG . 7 is a representative graph depicting a com COM compared to pooled placebo in accordance with the parison between quit rates after 4 weeks of abstinence present technology. compared to a quit rate during continuous abstinence ( weeks [ 0044 ] FIG . 22 is a representative plot depicting EMAs for 5-8 ) in the subject population of Example 1 in accordance continued 4 -week abstinence through Week 5 to Week 8 , with the present technology , confirmed by expired CO of < 10 ppm ( Cess / W5-8 / CO US 2021/0077475 A1 Mar. 18 , 2021 3

Success ) across clinical sites for cytisine 1.5 mg TID com Week 5 to Week 8 , confirmed by expired CO of < 10 ppm pared to pooled placebo in accordance with the present ( Cess / W5-8 / CO Success ) for cytisine 3.0 mg TID arm technology. compared to the pooled placebo arm in accordance with the [ 0045 ] FIG . 23 is a representative plot depicting EMAs for present technology. continued 4 -week abstinence through Week 5 to Week 8 , [ 0055 ] FIG . 33 is a schematic of the study design of confirmed by expired CO of < 10 ppm ( Cess / W5-8 / CO Example 2 in accordance with the present technology. Success ) across clinical sites for cytisine 3.0 mg TID com pared to pooled placebo in accordance with the present DETAILED DESCRIPTION technology . [ 0056 ] While the present disclosure is capable of being [ 0046 ] FIG . 24 is a representative plot depicting EMAs for embodied in various forms, the description below of several continued 4 -week abstinence through Week 5 to Week 8 , embodiments is made with the understanding that the pres confirmed by expired CO of < 10 ppm ( Cess / W5-8 / CO ent disclosure is to be considered as an exemplification of Success ) across clinical sites for cytisine 1.5 mg COM the invention and is not intended to limit the invention to the compared to pooled placebo in accordance with the present specific embodiments illustrated. Headings are provided for technology. convenience only and are not to be construed to limit the [ 0047 ] FIG . 25 is a representative plot depicting EMAs for invention in any manner . Embodiments illustrated under any continued 4 -week abstinence through Week 5 to Week 8 , heading may be combined with embodiments illustrated confirmed by expired CO of < 10 ppm ( Cess / W5-8 / CO under any other heading. Success ) across clinical sites for cytisine 3.0 mg COM [ 0057 ] The use of numerical values in the various quan compared to pooled placebo in accordance with the present titative values specified in this application , unless expressly technology indicated otherwise, are stated as approximations as though [ 0048 ] FIG . 26 is a representative plot depicting EMAs for the minimum and maximum values within the stated ranges Cigarette Score across baseline ( race, Hispanic, sex , age were both preceded by the word “ about. ” It is to be under ( M ) , age ( T ) , strat BMI , smoke Hx Dur ( y ) ( M ) , smoke Hx stood , although not always explicitly stated , that all numeri Dur ( y ) ( T ) , smoke Hx Dur ( y ) ( Q ) , > 2 Quit Hx , Screen cal designations are preceded by the term “ about. ” It is to be Mean Cigs / d ( M ) ) attributes for cytisine 3.0 mg TID com understood that such range format is used for convenience pared to pooled placebo in accordance with the present and brevity and should be understood flexibly to include technology . numerical values explicitly specified as limits of a range , but [ 0049 ] FIG . 27 is a representative plot depicting EMAs for also to include all individual numerical values or sub -ranges continued 4 -week abstinence through Week 5 to Week 8 , encompassed within that range as if each numerical value confirmed by expired CO of < 10 ppm ( Cess / W5-8 / CO and sub - range is explicitly specified . For example, a ratio in Success ) across baseline attributes ( race, Hispanic , sex , age the range of about 1 to about 200 should be understood to ( M ) , age ( T ) , strat BMI , smoke Hx Dur ( y ) ( M ) , smoke Hx include the explicitly recited limits of about 1 and about 200 , Dur ( y ) ( T ) , smoke Hx Dur ( y ) ( Q ) , > 2 Quit Hx , Screen but also to include individual ratios such as about 2 , about Mean Cigs / d ( M ) ) for cytisine 3.0 mg TID compared to 3 , and about 4 , and sub - ranges such as about 10 to about 50 , pooled placebo in accordance with the present technology. about 20 to about 100 , and so forth . It also is to be [ 0050 ] FIG . 28 is a representative plot depicting EMAs for understood , although not always explicitly stated , that the Cigarette Score across prior anti - smoking interventions ( > 2 reagents described herein are merely exemplary and that Quit Tx , Chantix® Hx , Zyban® Hx , Vape Hx , NRT Hx , equivalents of such are known in the art . Chantix® ( most recent ), Zyban® ( most recent ), Vape ( most [ 0058 ] The term out, ” as used herein when referring to recent ), and NRT ( most recent) for cytisine 3.0 mg TID ) a measurable value such as an amount or concentration and compared to pooled placebo in accordance with the present the like , is meant to encompass variations of 20 % , 10 % , 5 % , technology. 1 % , 0.5 % or even 0.1 % of the specified amount. [ 0051 ] FIG . 29 is a representative plot depicting EMAs for [ 0059 ] Also , the disclosure of ranges is intended as a continued 4 -week abstinence through Week 5 to Week 8 , continuous range , including every value between the mini confirmed by expired CO of < 10 ppm ( Cess / W5-8 / CO mum and maximum values recited , as well as any ranges Success ) across prior anti- smoking interventions ( > 2 Quit that can be formed by such values . Also disclosed herein are Tx , Chantix® Hx , Zyban® Hx , Vape Hx , NRT Hx , Chan any and all ratios ( and ranges of any such ratios) that can be tix® ( most recent ), Zyban® ( most recent) , Vape ( most formed by dividing a disclosed numeric value into any other recent ), and NRT ( most recent )) for cytisine 3.0 mg TID disclosed numeric value . Accordingly, the skilled person compared to pooled placebo in accordance with the present will appreciate that many such ratios, ranges, and ranges of technology . ratios can be unambiguously derived from the numerical [ 0052 ] FIG . 30 is a representative plot depicting EMAs for values presented herein and in all instances , such ratios , Cigarette Score across baseline laboratory markers ( NMR , ranges , and ranges of ratios represent various embodiments CO , cotinine ) for cytisine 3.0 mg TID compared to pooled of the present disclosure . placebo in accordance with the present technology . [ 0060 ] The phrase " statistical significance , ” as used herein [ 0053 ] FIG . 31 is a representative plot depicting EMAs for refers to a result from data generated by testing or experi continued 4 -week abstinence through Week 5 to Week 8 , mentation, is not likely to occur randomly or by chance, but confirmed by expired CO of < 10 ppm ( Cess / W5-8 / CO is instead likely to be attributable to a specific cause . Success ) across baseline laboratory markers (NMR , CO , Statistical significance is evaluated from a calculated prob cotinine ) for cytisine 3.0 mg TID compared to pooled ability ( p -value ), where the p - value is a function of the placebo in accordance with the present technology . means and standard deviations of the data samples and [ 0054 ] FIG . 32 is a representative graph depicting tipping indicates the probability under which a statistical result point analysis for continued 4 - week abstinence through occurred by chance or by sampling error . A result is con US 2021/0077475 A1 Mar. 18 , 2021 4 sidered statistically significant if the p - value is 0.05 or less , of vapor taken or otherwise consumed from the vaping corresponding to a confidence level of 95 % . device , a reduction in a number or a frequency of vaping [ 0061 ] “ Comprising " or " comprises" is intended to mean session performed with the vaping device , or a reduction in that the compositions and methods include the recited ele use of the vaping device to ingest vapor. ments , but not excluding others . " Consisting essentially of" [ 006 ] As used herein , the term " adverse event ” ( AE ) when used to define compositions and methods, shall mean refers to any untoward medical occurrence in a subject excluding other elements of any essential significance to the administered a composition and which does not necessarily combination for the stated purpose . Thus, a composition have attribution with the treatment. An AE can therefore be consisting essentially of the elements as defined herein any unfavorable and unintended sign ( including an abnormal would not exclude other materials or steps that do not laboratory finding ), symptom , or disease temporally associ materially affect the basic and novel characteristic (s ) of the ated with the use of the composition , whether or not con claimed invention . “ Consisting of" shall mean excluding sidered related to the composition . more than trace elements of other ingredients and substantial [ 0067 ] As used herein , the term “ adverse drug reaction ” method steps . Embodiments defined by each of these tran refers to any untoward and unintended responses to the sition terms are within the scope of this invention . administered composition . The term “ response to the com [ 0062 ] The phrase " control subject , ” as used herein refers position " means that attribution has at least a reasonable to any subject used as a basis for comparison to the test possibility ( i.e. , the relationship cannot be ruled out and is subject. A control subject includes , but is not limited to , any judged by the investigator as at least possible ) ( see definition subject who has not been administered the composition , below ). administered a composition other than the test composition [ 0068 ] The terms “ serious adverse event " ( SAE ) and “ seri ( e.g. , 1.5 mg of cytisine three times per day or 3.0 mg of ous adverse reaction ” ( SAR ) refer to an AE that results in at cytisine three times per day ), or administered a placebo . least one of the following AEs : death , life - threatening, [ 0063 ] The term “ treatment” in relation to a given disease requires hospitalization or prolongs a subject's existing or disorder, includes , but is not limited to , inhibiting the hospitalization , results in persistent or significant disability disease or disorder, for example, arresting the development or incapacity , results in a congenital abnormality or birth of the disease or disorder; relieving the disease or disorder, defect, or is an important medical event which requires for example, causing regression of the disease or disorder; or medical intervention to prevent any of the foregoing out relieving a condition caused by or resulting from the disease comes . or disorder, for example , relieving or treating symptoms of [ 0069 ] As used herein , the term “ suspected unexpected the disease or disorder. The term “ prevention ” in relation to serious adverse reactions ” ( SUSARs ) are AEs which are a given disease or disorder means : preventing the onset of serious, unexpected, and there is at least a reasonable disease development if none had occurred , preventing the possibility that there is attribution between the event and the disease or disorder from occurring in a subject that may be composition . Important medical events are those which may predisposed to the disorder or disease but has not yet been not be immediately life -threatening but may jeopardize the diagnosed as having the disorder or disease , and / or prevent subject and may require intervention to prevent one of the ing further disease / disorder development if already present. other serious outcomes listed above . Examples of such [ 0064 ] “ Vaping ” refers to the act of a subject inhaling events are intensive treatment in an emergency room or at vapor created by a device from a solution carried in a home for allergic bronchospasm , or blood dyscrasias or cartridge or a chamber. In some embodiments , the device is convulsions that do not result in hospitalization . The term electronic and simulates smoking . Vaping devices can “ life - threatening” refers to an event in which the subject was include , but are not limited , to a power source , an atomizer, at risk of death at the time of the event; it does not refer to and the cartridge or chamber. In some embodiments, vaping an event which hypothetically might have caused death if it refers to consumption of ejuice or vaping activity , such as were more severe . For example, drug - induced hepatitis that taking or otherwise consuming puffs of vapor from the resolves without evidence of hepatic failure would not be vaping device, performing a vaping session with the vaping considered life threatening even though drug - induced hepa device , or otherwise using the vaping device to ingest vapor . titis can be fatal. Inpatient hospitalization or prolongation of In another embodiment, vaping refers to consumption of existing hospitalization means that hospital inpatient admis ejuice. In an alternative embodiment, vaping refers to con sion and / or prolongation of hospital stay were required for sumption of ejuice or taking or otherwise consuming puffs treatment of AE or occurred as a consequence of the event . of vapor from the vaping device . In yet another embodiment, It does not refer to pre - planned elective hospital admission vaping refers to vaping activity . In other embodiments , for treatment of a pre -existing condition that has not sig vaping refers to taking or otherwise consuming puffs of nificantly worsened , or to diagnostic procedures. vapor from the vaping device, performing a vaping session [ 0070 ] The terms " cytisine - treated arm , ” “ active arms, ” with the vaping device , or otherwise using the vaping device " treatment arm ," " active treatment arm , " and " investiga to ingest vapor . In further embodiments , vaping refers to tional arm ” are used interchangeably throughout and refer to taking or otherwise consuming puffs of vapor from the subjects administered a composition comprising cytisine . vaping device or otherwise using the vaping device to ingest [ 0071 ] List of abbreviations: ADR , Adverse Drug Reac vapor. In still further embodiments , vaping refers to using tion ; AE , Adverse Event; ALT, Alanine Aminotransferase ; the vaping device to ingest vapor. AST, Aspartate Aminotransferase ; BMI , Body Mass Index ; [ 0065 ] As used herein , the terms “ reduction in vaping , " Cmax , Maximum Observed Plasma Concentration ; Crci, “ reduced vaping, ” and “ reduces vaping” refers to decreasing Creatinine Clearance ; CRF , Case Report Form ; DSM , Data a frequency or amount of vaping per hour, per day, per week , Safety Monitor ; ECG , Electrocardiogram ; GCP, Good Clini per month , or per year, such as reducing an amount of ejuice cal Practice ; ICH , International Conference on Harmoniza consumed , a reduction in a number or a frequency of puffs tion ; IMP, Investigational Medicinal Product ( for this pro US 2021/0077475 A1 Mar. 18 , 2021 5 tocol , indicates cytisinicline 3.0 mg film coated tablet ); can be employed in the compositions include , for example , MedDRA , Medical Dictionary for Regulatory Activities ; fillers, disintegrants, preserving agents, lubricants, and wet SAE , Serious Adverse Event; SAR , Serious Adverse Reac ting agents . tion ; SmPC , Summary of Product Characteristics; SOC , [ 0078 ] Examples of fillers that can be used include lactose MedDRA System Organ Class ; SUSAR , Suspected Unex ( for example, either anhydrous or monohydrate ), cellulose , pected Serious Adverse Reaction ; Tmax , Time to Maximum starch ( for example, corn and / or wheat starch ), calcium Observed Concentration ; UADR , Unexpected Adverse Drug phosphates, calcium sulfates, and mannitol. Reaction ; UAE , Unexpected Adverse Event; ULN , Upper [ 0079 ] Preserving agents prevent bacterial or fungal con Limit of Normal. tamination of the formulation and include various antibac terial and antifungal agents, such as parabens, chlorobuta Compositions nol , phenol, and sorbic acid . [ 0080 ] Suitable lubricants include stearic acid and its salts . [ 0072 ] A composition for use in methods of the disclosure One example of a lubricant for use in the compositions of the comprises cytisine or a pharmaceutically acceptable deriva disclosure is magnesium stearate . tive , conjugate , or salt thereof, or mixtures of any of the [ 0081 ] The pharmaceutical compositions can further com foregoing, collectively referred to herein as " cytisine . ” The prise sweetening , flavoring, or coloring agents . term “ pharmaceutically acceptable " in the present context [ 0082 ] In some embodiments, the placebo is a tablet which means that the substance in question does not produce comprises the same , substantially the same, similar, or unacceptable toxicity to the subject or interaction with other substantially similar non -active ( e.g., cytisine ) components components of the composition. Cytisine, ( - ) - cytisine, and to the test composition . In these embodiments, the placebo cytisinicline are referenced interchangeably. comprises at least the same , substantially the same , similar, or substantially similar excipients , fillers, preserving agents , [ 0073 ] Any suitable cytisine pharmaceutical composition lubricants, sweetening, flavoring, and / or coloring agents as or formulation can be used in the methods described herein . the test composition , as well as at least one other non - active In some embodiments, cytisine can be formulated in tablet component, such as cellulose . In some embodiments, the form , for example , as compressed film -coated tablets for placebo tablet and the test composition tablet are the same oral administration . or substantially the same weight, size , shape , color, and / or [ 0074 ] A composition for use in accordance with the are contained in the same or substantially the same pack disclosure can be formulated as one or more dosage units . aging. The terms " dose unit" and " dosage unit " herein refer to a [ 0083 ] A person skilled in the art will be well aware of portion of a pharmaceutical composition that contains an suitable fillers, preserving agents, and lubricants other than amount of a therapeutic agent suitable for a single admin those specifically mentioned above , as well as suitable istration to provide a therapeutic effect . Such dosage units sweetening, flavoring, and coloring agents, and other addi may be administered one to a plurality ( i.e. , 1 to about 10 , tives . The pharmaceutical compositions of cytisine useful in 1 to 8 , 1 to 6 , 1 to 4 , 1 to 3 , or 1 to 2 ) of times per day, or the methods of the disclosure can comprise a coating, for as many times as needed to elicit a therapeutic response . example , a film coating, and can be coated according to any [ 0075 ] The unit dose can comprise a single tablet, such as method known in the art, for example, using collidone , a tablet containing 3.0 mg of cytisine, or it can comprise two shellac , gum arabic , talc , titanium dioxide , or sugar . or more tablets which together contain the unit dose ( e.g. , [ 0084 ] The pharmaceutical compositions comprising 3.0 mg of cytisine ) . For example, the unit dose of 3.0 mg can cytisine can be prepared by any suitable method . For comprise two tablets, each containing 1.5 mg of cytisine, example, capsules can be prepared by mixing cytisine with such as two Tabex® tablets . Each Tabex® tablet is typically one or more inert carriers such as lactose or sorbitol and formulated as a compressed film - coated tablet containing packing into gelatin capsules . Tablets can be made by known 1.5 mg of cytisine in a single tablet together with a number compression methods . of tablet - forming excipients ( calcium sulfate, cellulose pow [ 0085 ] In one embodiment, compositions of the disclo der, colloidal silica , magnesium stearate ) and coated with a sure, upon storage in a closed container maintained at room colored film - coat , including polyvinyl alcohol , titanium temperature, refrigerated ( e.g. , about 5 ° C. to about -10 ° C. ) dioxide , and iron oxides . As another example , the unit dose temperature , or frozen for a period of about 1 , 2 , 3 , 4 , 5 , 6 , of 3.0 mg can comprise three tablets , each containing 1.0 mg 7 , 8 , 9 , 10 , 11 , or 12 months , exhibit at least about 90 % , at of cytisine , such as three tablets formulated at least similarly least about 95 % , at least about 97.5 % , or at least about 99 % to the Tabex® tablets . of the active ingredient( s ) originally present therein . [ 0076 ] Alternatively , the cytisine may be formulated in a capsule or another vehicle for oral administration and are Methods orally deliverable ; or in a composition for nasal or topical [ 0086 ] The disclosure provides treating a nicotine addic administration . The terms " orally deliverable ” or “ oral tion or a nicotine dependence in a subject in need thereof, administration ” herein include any form of delivery of a comprising administering the subject an effective amount of therapeutic agent or a composition thereof to a subject cytisine. In some embodiments, the methods of treating a wherein the agent or composition is placed in the mouth of nicotine addiction or a nicotine dependence include prevent the subject, whether or not the agent or composition is ing smoking relapse and / or promoting cessation of or reduc swallowed . Thus, “ oral administration ” includes buccal and tion in smoking in the subject in need thereof. sublingual, as well as esophageal administration . [ 0087 ] In some embodiments, the disclosure provides [ 0077 ] The tablets and other dosage forms ( hereinafter all methods of treating nicotine addiction or a nicotine depen referred to as " compositions ” ) can contain one or more dence in a subject in need thereof, comprising administering excipients, such as those common in the art . Excipients that to the subject a therapeutically effective amount of cytisine. US 2021/0077475 A1 Mar. 18 , 2021 6

In some embodiments, present disclosure relates to methods ing in a subject in need thereof, comprising administering to for preventing smoking relapse in a subject in need thereof, the subject a therapeutically effective amount of cytisine . In comprising administering to the subject a therapeutically some embodiments , the disclosure provides methods for effective amount of cytisine . In another embodiment, the promoting a reduction in vaping of a subject in need thereof, disclosure provides methods of promoting cessation of comprising administering to the subject a therapeutically smoking in a subject in need thereof, comprising adminis effective amount of cytisine. tering to the subject a therapeutically effective amount of [ 0090 ] In some embodiments , provided herein is a method cytisine. In some embodiments, the disclosure provides of treating of nicotine addiction or a nicotine dependence in methods for promoting a reduction in smoking of a subject a subject, comprising administering cytisine in equal dosage in need thereof, comprising administering to the subject an amounts two times per day (“ bid ” or “ BID ' ) or three times effective amount of cytisine . In some embodiments, the per day ( “ tid ” or “ TID ” ) to a subject in need thereof. In one disclosure provides methods of treating nicotine addiction or embodiment, each of the two daily administrations occur a nicotine dependence in a subject in need thereof, wherein morning and evening, respectively . In another embodiment, the nicotine addiction or a nicotine dependence is in the form each of the two daily administrations occur in approximate of cigarettes, smokeless tobacco , snus, electronic cigarettes intervals of 10-12 hours . In yet another embodiment, each of ( e - cigs ) , vapes such as vaping using a vaping device, and / or the three daily administrations occur morning, noon , and hookah . In some embodiments , the vaping device includes a evening , respectively. In another embodiment, each of the liquid comprising nicotine, for example, about 1 mg/ ml three daily administrations occur in approximate intervals of nicotine to about 12 mg/ ml nicotine or greater than about 13 4-5 hours . In yet another embodiment, each of the three daily mg/ ml nicotine . Any patient with nicotine addiction or a administrations occur in approximate intervals of 4 hours, 5 nicotine dependence can be treated by the methods disclosed hours , 6 hours , 7 hours, 8 hours , 9 hours, 10 hours, or more . herein . In one embodiment, the administration occurs for a period of [ 0088 ] In additional embodiments, the disclosure provides at least about 6 weeks , at least about 12 weeks , at least about methods of treating and / or preventing an addiction or a 24 weeks , or indefinitely. In this embodiment, the adminis dependence in a subject in need thereof, comprising admin tration can include BID or TID for any period of days or istering to the subject a therapeutically effective amount of weeks during the administration . For example , in these cytisine. Without intending to be bound by any particular embodiments, the entire period of administration can be BID theory, it is thought that cytisine interacts with the dopamine or TID . As another example, in these embodiments , at least neurotransmitter release cycle as a partial agonist of nico a portion of the administration can be BID or TID , such as tinic acetylcholine receptors ( NACHRs) and is useful for at least about one day, at least about three days, at least about treating and / or preventing a plurality of addictions or plu one week , at least about two weeks , at least about four rality of dependences in a subject in need thereof. Non weeks, at least about 12 weeks . As yet another example, in limiting examples of addictions and dependencies that are these embodiments, the BID or TID administration can thought to be treated and / or prevented by administration of occur in any order, such as Day 1 can be BID or TID , Day cytisine includes addictions and / or dependencies to sub 2 can be BID or TID , Day 3 can be BID or TID , and so on stances, compounds, and / or behaviors that may involve the for the period of administration . dopamine neurotransmitter release cycle . Exemplary sub [ 0091 ] In some embodiments, the administration occurs stances, compounds, and / or behaviors includes, but is not independent of whether the subject is in a fed or fasted state . limited to , marijuana, cannabis, tetrahydrocannabinol For example, the administration can occur simultaneously ( THC ) , cannabidiol ( CBD ) , alcohol, opioids and other pain with food , concurrently with food , any amount of time killers , cocaine , eating, gambling, sex , heroin , benzodiaz before the subject ingests food , or any amount of time after epines , barbiturates, stimulants, and inhalants. In further the subject ingests food . Without intending to be limited to embodiments, the disclosure provides methods of promoting any particular theory , it is not thought that food ( or a fed cessation of the addiction or the dependence in a subject in state or a fasted state) impacts the bioavailability of cytisine need thereof, comprising administering to the subject a which can be determined by an overall body absorption or therapeutically effective amount of cytisine . In some overall bioavailability of cytisine in the subject. embodiments , the disclosure provides methods for promot [ 0092 ] In some embodiments , the TID dose is 1 mg, 1.5 ing a reduction in a subject's addiction and / or dependence , mg , 2 mg , 2.5 mg , or 3.0 mg of cytisine. In some embodi comprising administering to the subject an effective amount ments, the TID dose is 1 mg , regardless of how the dose is of cytisine . The compositions and methods described herein divided . For example, each TID dose could be given in two with respect to smoking , vaping, and nicotine can be used to 0.5 mg strength tablets administered 3 times per day or in treat , prevent, and / or reduce addiction or dependence in the one 1 mg tablet administered three times per day , or any subject in need thereof, such as any subject having an other possibility . In some embodiments, the TID dose is 1.0 addiction or a dependence involving the dopamine neu mg , regardless of how the dose is divided among dosage rotransmitter release cycle . units . In some embodiments , the TID dose is 1.5 mg , [ 0089 ] In further embodiments , the methods of treating a regardless of how the dose is divided among dosage units. nicotine addiction or a nicotine dependence include prevent In some embodiments, the TID dose is 2 mg , regardless of ing vaping relapse and / or promoting cessation of or reduc how the dose is divided among dosage units . In yet another tion in vaping in the subject in need thereof. In some embodiment, the TID dose is 2.5 mg , regardless of how the embodiments, the present disclosure relates to methods for dose is divided among dosage units . In some embodiments , preventing vaping relapse in a subject in need thereof, the TID dose is 3.0 mg , regardless of how the dose is divided comprising administering to the subject a therapeutically among dosage units. effective amount of cytisine . In another embodiment, the [ 0093 ] In some embodiments, the subject experiences no disclosure provides methods of promoting cessation of vap adverse events related to the cytisine treatment. Adverse US 2021/0077475 A1 Mar. 18 , 2021 7 events can be mild ( e.g , no interference with activity ) , at least about 75 % , at least about 80 % , at least about 85 % , moderate ( some interference with activity but requiring no at least about 90 % , at least about 95 % , or at least about or minimal medical intervention ), or severe (prevents daily 100 % as compared to a control subject, placebo control, activity and requires medical intervention ). Non - limiting and /or baseline after treatment with 1.0 mg TID , 1.5 mg examples of adverse events include an upper respiratory TID , or 3.0 mg TID of cytisine. tract infection (URTI ) , abnormal dreams, nausea, insomnia, [ 0096 ] In some embodiments, the administration of headache , fatigue, and constipation. In other embodiments, cytisine increases abstinence in the subject after treatment the subject experiences two or fewer adverse events related with 1.0 mg TID , 1.5 mg TID , or 3.0 mg TID of cytisine. In to the cytisine treatment, such as , an increase in the occur these embodiments, the subject has increased abstinence of rence of nausea , abnormal dreams, insomnia, headache, about 5 % to about 30 % , for example , about 5 % to about and / or URTI in a subject from about 0 % to about 10 % , for 15 % , about 5 % to about 10 % , about 5 % to about < 10 % , example , about 0 % , about 1 % , about 2 % , about 3 % , about about 10 % to about 25 % , about 15 % to about 20 % , about 4 % , about 5 % , about 6 % , about 7 % , about 8 % , about 9 % , or 20 % to about 30 % , or about 25 % to about < 30 % , about 5 % about 10 % . In some embodiments, the subject experiences to about 100 % , about 5 % to about 75 % , about 5 % to about no adverse events as compared to a subject administered a 50 % , about 25 % to about 75 % , about 25 % to about 50 % , nicotine replacement therapy ( NRT ), bupropion , vareni about 30 % to about 50 % , about 30 % to about 50 % , about cline, electronic cigarettes, vaping , and / or combination 30 % to about 75 % , about 30 % to about < 100 % , or about thereof. 30 % to about 100 % , such as at least about 10 % , at least [ 0094 ] In some embodiments, the subject experiences about 15 % , at least about 20 % , at least about 25 % , at least nicotine addiction or a nicotine dependence by smoking about 30 % , at least about 35 % , at least about 40 % , at least cigarettes, ingesting smokeless tobacco and / or snus, using about 45 % , at least about 50 % , or at least about 55 % electronic cigarettes ( e - cigs ) and / or vapes, and / or using following cytisine treatment relative to an abstinence hookah daily , such as a per unit consumption of nicotine per achieved without cytisine treatment. In some embodiments, day . In some embodiments , the subject having nicotine abstinence is a period of abstinence , such as about a 2 week addiction or a nicotine dependence consumes about 0 to abstinence, about a 3 week abstinence , about a 4 week about 100 units of nicotine per day. For example , a single abstinence , about a 5 week abstinence, about a 6 week cigarette may be a unit of nicotine and the subject having the abstinence, about a 7 week abstinence, about an 8 week nicotine addiction or a nicotine dependence smokes about 0 abstinence , about a 12 week abstinence , about a 16 week cigarettes per day to about 100 cigarettes per day, about 5 abstinence , about a 20 week abstinence, about a 24 week cigarettes per day to about 75 cigarettes per day, about 5 abstinence , about a 28 week abstinence , or about a 32 week cigarettes per day to about 50 cigarettes per day, about 5 abstinence . In certain embodiments, the period of abstinence cigarettes per day to about 25 cigarettes per day, about 10 is about 1 day to about 4 weeks, from about 1 week to about cigarettes per day to about 50 cigarettes per day , about 20 8 weeks , from about 2 weeks to about 12 weeks, from about cigarettes per day to about 50 cigarettes per day , about 25 4 weeks to about 24 weeks , or from about 8 weeks to about cigarettes per day to about 75 cigarettes per day, about 25 32 weeks . cigarettes per day to about 50 cigarettes per day, for [ 0097 ] In some embodiments, administration of cytisine example , about 0 cigarettes per day , about 1 cigarette per increases a quit rate in the subject after treatment with 1.0 day, about 2 cigarettes per day, about 3 cigarettes per day, mg TID , 1.5 mg TID , or 3.0 mg TID of cytisine . In these about 4 cigarettes per day, about 5 cigarettes per day, about embodiments, the subject has a quit rate of about 5 % to 6 cigarettes per day, about 7 cigarettes per day, about 8 about 30 % , for example, about 5 % to about 15 % , about 5 % cigarettes per day, about 9 cigarettes per day, about 10 to about 10 % , about 5 % to about < 10 % , about 10 % to about cigarettes per day, about 11 cigarettes per day, about 12 25 % , about 15 % to about 20 % , about 20 % to about 30 % , or cigarettes per day, about 13 cigarettes per day, about 14 about 25 % to about < 30 % , about 5 % to about 100 % , about cigarettes per day, about 15 cigarettes per day , about 16 5 % to about 75 % , about 5 % to about 50 % , about 25 % to cigarettes per day, about 17 cigarettes per day, about 18 about 75 % , about 25 % to about 50 % , about 30 % to about cigarettes per day, about 19 cigarettes per day, about 20 50 % , about 30 % to about 50 % , about 30 % to about 75 % , cigarettes per day, about 25 cigarettes per day , about 30 about 30 % to about < 100 % , or about 30 % to about 100 % , cigarettes per day, about 35 cigarettes per day , about 40 such as at least about 10 % , at least about 15 % , at least about cigarettes per day, about 45 cigarettes per day , about 50 20 % , at least about 25 % , at least about 30 % , at least about cigarettes per day, about 55 cigarettes per day, about 60 35 % , at least about 40 % , at least about 45 % , at least about cigarettes per day, about 65 cigarettes per day , about 70 50 % , or at least about 55 % after a 4 week abstinence or cigarettes per day, about 75 cigarettes per day, about 80 during continuous abstinence during weeks 5-8 following cigarettes per day, about 85 cigarettes per day, about 90 cytisine treatment. In some embodiments , quit rate is deter cigarettes per day, or about 100 cigarettes per day . In other mined after a period of abstinence , such as about a 1 day examples, units of nicotine also include ingesting smokeless abstinence , about a 3 day abstinence, about a 7 day absti tobacco and / or snus , using electronic cigarettes ( e - cigs ) nence , about a 10 day abstinence, about a 2 week abstinence , and / or vapes ( e.g. , vaping ) , and / or using hookah instead of about a 3 week abstinence , about a 4 week abstinence , about or in combination with cigarettes daily . a 5 week abstinence, about 6 week abstinence , about a 7 [ 0095 ] In some embodiments, administration of cytisine week abstinence, about an 8 week abstinence , about a 9 reduces the number of units of nicotine a subject ingests per week abstinence , about a 10 week abstinence , about an 11 day, such as a number of cigarettes a subject smokes per day . week abstinence, about a 12 week abstinence , about a 16 In some embodiments , the methods of the present technol week abstinence , about a 20 week abstinence , about a 24 ogy reduce a percentage of cigarettes smoked by the subject week abstinence , about a 28 week abstinence, or about a 32 by at least about 60 % , at least about 65 % , at least about 70 % , week abstinence . In certain embodiments, the period of US 2021/0077475 A1 Mar. 18 , 2021 8 abstinence is about 1 day to about 4 weeks , from about 1 about 85 % , at least about 90 % , at least about 95 % , or at least week to about 8 weeks , from about 1 week to about 2 weeks , about 100 % as compared to a control subject, placebo from about 3 weeks to about 6 weeks , from about 2 weeks control, and / or baseline . In some embodiments , the subject to about 12 weeks , from about 9 weeks to about 12 weeks , has serum and / or plasma cotinine levels of about 0.1 ng /mL from about 4 weeks to about 24 weeks, or from about 8 to about 20 ng /mL , about 0.1 ng /mL to about 15 ng /mL , weeks to about 32 weeks . about 0.5 ng /mL to about 10 ng /mL , about 1 ng /mL to about [ 0098 ] In some embodiments, the subject has expired CO 10 ng /mL , about 0.5 ng /mL to about 5 ng /mL , or about 0.5 levels of about 0 ppm to about 50 ppm , for example, about ng /mL to about 1 ng /mL , for example, about 0.1 ng / mL , 10 ppm to about 40 ppm , about 10 ppm to about 30 ppm , about 0.5 ng /mL , about 1 ng /mL , about 1.5 ng /mL , about 3 about 10 ppm to about < 20 ppm , about 20 ppm to about 30 ng /mL , about 5 ng /mL , about 7 ng /mL , about 8 ng / mL , ppm , about 20 ppm to about 40 ppm , about 20 ppm to about about 9 ng /mL , about 10 ng /mL , about 15 ng / mL , or about < 50 ppm , or about 20 ppm to about 50 ppm , for example, 20 ng /mL after treatment with cytisine. about 0 ppm , about 2 ppm , about 4 ppm , about 6 ppm , about 8 ppm , about 10 ppm , about 12 ppm , about 14 ppm , about [ 0100 ] In some embodiments , administration of cytisine 16 ppm , about 18 ppm , about 20 ppm , about 22 ppm , about increases an odds ratio in the subject after treatment with 1.0 24 ppm , about 26 ppm , about 28 ppm , about 30 ppm , about mg TID , 1.5 mg TID , or 3.0 mg TID of cytisine for 4 weeks 32 ppm , about 34 ppm , about 36 ppm , about 38 ppm , about of treatment, after 8 weeks of treatment, and 4 weeks after 40 ppm , about 42 ppm , about 44 ppm , about 46 ppm , about treatment ends. In these embodiments, the subject has an 48 ppm , or about 50 ppm before treatment with cytisine . In odds ratio of about 1.1 to about 20 , about 1.1 to about 15 , some embodiments, administration of 1.0 mg TID , 1.5 mg about 1.1 to about 10 , about 1.1 to about 5 , about 5 to about TID , or 3.0 mg TID of cytisine , or treatment with 1.0 mg 10 , about 5 to about 15 , about 10 to about 15 , about 10 to TID , 1.5 mg TID , or 3.0 mg TID of cytisine , reduces a level about < 20 , or about 10 to about 20 as compared to a control of expired CO by the subject by at least about 60 % , at least subject, placebo control, and / or baseline . about 65 % , at least about 70 % , at least about 75 % , at least [ 0101 ] In some embodiments, the subject's vital signs , about 80 % , at least about 85 % , at least about 90 % , at least hematology and chemistry levels, and ECG are measured about 95 % , or at least about 100 % as compared to a control prior to and / or after administration of cytisine . In some subject, placebo control, and / or baseline . In some embodi embodiments, the subject exhibits no clinically - significant ments , the subject has expired CO levels of about 0 ppm to changes in vital signs , hematology and chemistry levels, and about 30 ppm , for example, about 10 ppm to about 25 ppm , ECG after administration of cytisine. about 10 ppm to about 20 ppm , about 10 ppm to about < 20 ppm , about 5 ppm to about 15 ppm , about 5 ppm to about [ 0102 ] In some embodiments , the subject is a heavy , 10 ppm , about 1 ppm to about < 10 ppm , or about 10 ppm to moderate , or light nicotine user , such as a smoker or a vaper about 5 ppm , for example about 0 ppm , about 2 ppm , about using nicotine can be categorized as a “ heavy smoker” or 4 ppm, about 6 ppm , about 8 ppm , about 10 ppm , about 12 “ heavy vaper , ” a “ moderate smoker ” or “ moderate vaper, " or ppm , about 14 ppm , about 16 ppm , about 18 ppm , or about a “ light smoker ” or “ light vaper .” For example , a “ heavy 20 ppm after treatment with cytisine. smoker ” as provided herein refers to a subject who reports [ 0099 ] In some embodiments , the subject has serum and / consuming 20 or more cigarettes per day. A " moderate or plasma cotinine levels of about 5 ng /mL to about 500 smoker ” as provided herein refers to a subject who reports ng /mL , about 25 ng /mL to about 400 ng /mL , about 25 consuming 11-19 cigarettes per day. A “ light smoker ” as ng /mL to about 400 ng /mL , about 25 ng /mL to about 300 provided herein refers to a subject who reports consuming ng /mL , about 50 ng /mL to about 200 ng /mL , about 75 1-10 cigarettes per day . As another example , a " heavy vaper " ng /mL to about 150 ng /mL , about 85 ng /mL to about 100 as provided herein refers to a subject who reports perform ng /mL , about 100 ng /mL to about 400 ng /mL , about 100 ing 20 or more vaping sessions per day, consuming 20 or ng /mL to about 300 ng /mL , about 100 ng /mL to about 200 more puffs from a vaping device per day, or otherwise ng /mL , about 200 ng /mL to about 300 ng /mL , about 200 reports 20 or more uses of a vaping device per day . A ng /mL to about 400 ng /mL , about 200 ng /mL to about < 500 “ moderate vaper" as provided herein refers to a subject who ng /mL , about 200 ng /mL to about 500 ng /mL , for example , reports performing 11-19 vaping sessions per day , consum about 10 ng /mL , about 20 ng /mL , about 30 ng /mL , about 40 ing 11-19 puffs from a vaping device per day, or otherwise ng /mL , about 50 ng /mL , about 60 ng /mL , about 70 ng / mL , reports 11-19 uses of a vaping device per day. A “ light about 80 ng /mL , about 90 ng /mL , about 100 ng /mL , about vaper " as provided herein refers to a subject who reports 125 ng /mL , about 150 ng /mL , about 175 ng /mL , about 200 performing 1-10 vaping sessions per day, consuming 1-10 ng /mL , about 225 ng /mL , about 250 ng /mL , about 275 puffs from a vaping device per day , or otherwise reports 1-10 ng /mL , about 300 ng / mL , about 325 ng /mL , about 350 uses of a vaping device per day. In some embodiments, ng /mL , about 375 ng /mL , about 400 ng /mL , about 425 administration of cytisine reduces cotinine levels in a subject ng /mL , about 450 ng /mL , about 475 ng /mL , or about 500 identified as a heavy smoker or a heavy vaper . In some ng /mL before treatment with cytisine. In some embodi embodiments, administration of cytisine reduces cotinine ments , administration of 1.0 mg TID , 1.5 mg TID , or 3.0 mg levels in a subject identified as a moderate smoker or a TID of cytisine, or treatment with 1.0 mg TID , 1.5 mg TID , moderate vaper. In yet another embodiment, administration or 3.0 mg TID of cytisine, reduces serum and / or plasma of cytisine reduces cotinine levels in a subject identified as cotinine levels in the subject by at least about 20 % , at least a light smoker or a light vaper . about 25 % , at least about 30 % , at least about 35 % , at least [ 0103 ] In some embodiments, the subject has been smok about 40 % , at least about 45 % , at least about 50 % , at least ing or vaping for at least about 1 year , at least about 5 years , about 55 % , at least about 60 % , at least about 65 % , at least at least about 10 years , at least about 15 years, at least about about 70 % , at least about 75 % , at least about 80 % , at least 20 years , at least about 25 years , at least about 30 years, at US 2021/0077475 A1 Mar. 18 , 2021 9 least about 35 years, at least about 40 years, at least about 45 pion , administration of varenicline , electronic cigarettes , years , at least about 50 years, or more , prior to administra vaping , or a combination thereof. tion of cytisine. [ 0111 ] In some embodiments , the subject has previously [ 0104 ] In some embodiments, the subject began smoking attempted to quit smoking or vaping at least 1 time , at least or vaping as an adolescent. 2 times , at least 3 times , at least 4 times , at least 5 times , at [ 0105 ] In some embodiments, the subject began smoking least 6 times , at least 7 times , at least 8 times , at least 9 times , cigarettes or vaping between the ages of 10 and 19. In some at least 10 times , or more prior to administration of cytisine. embodiments, the subject began smoking cigarettes or vap [ 0112 ] In some embodiments , the refractory subject has ing as an adolescent and has been smoking cigarettes or previously received nicotine addiction and / or nicotine vaping for at least about 20 years , at least about 25 years, at dependence treatment for at least about 1 week , about 2 least about 30 years , at least about 35 years, at least about 40 weeks, about 3 weeks, about 4 weeks, about 5 weeks , about years , at least about 45 years, at least about 50 years , or more 6 weeks, about 7 weeks , about 8 weeks , about 9 weeks, prior to administration of cytisine. about 10 weeks , about 11 weeks , or about 12 weeks prior to [ 0106 ] In some embodiments , the length of the adminis administration of cytisine . tration is up to about 26 weeks. In certain embodiments the [ 0113 ] In one aspect , the methods comprise administering length of the administration is from about 6 weeks to about cytisine to the subject, wherein the cytisine is provided in a 12 weeks , and in some embodiments , the cytisine is admin unit dose of about 1.0 mg to about 5.0 mg . In certain istered as described above for about 6 weeks . embodiments, the unit dose of cytisine is about 1.0 mg . In certain embodiments, the unit dose of cytisine is about 1.5 [ 0107 ] Compared with the commercial 25 -day titration mg . In certain embodiments , the unit dose of cytisine is schedule with unit doses of 1.5 mg of cytisine, the percent about 3.0 mg . In some embodiments , the unit dose of age of smokers with continuous abstinence is surprisingly cytisine is administered to the subject three to six times higher in the subjects treated according to the methods daily . In some embodiments, the unit dose of cytisine is disclosed herein , as demonstrated , for example , in FIG . 7 . administered to the subject three times per day . In some [ 0108 ] In some embodiments, the subject is a smoker, for embodiments of the methods disclosed herein , the unit dose example, a smoker who smokes about 3 or more cigarettes is either about 1.0 mg administered three times daily , about a day. In some embodiments, the subject is a smoker who 1.5 mg administered three times daily, or about 3.0 mg smokes about 5 or more or about 10 or more cigarettes a day . administered three times daily for about 1 week , about 2 In some embodiments, the subject has measurable expired weeks, about 3 weeks, about 4 weeks, about 5 weeks , about air CO concentration of about 10 ppm or greater prior to the 6 weeks, about 7 weeks , about 8 weeks , about 9 weeks, administration of cytisine . about 10 weeks, about 11 weeks, about 12 weeks , about 4 [ 0109 ] In some embodiments, the subject is a refractory months, about 1 year, about 1.25 years , about 1.5 years , patient. As used herein , a “ refractory patient ” or “ refractory about 1.75 years , about 2 years , or more than about 2 years . subject” is a subject who has failed treatment with one or In certain embodiments, the unit dose of cytisine is admin more nicotine addiction or nicotine dependence treatments . istered for up to about 2 weeks , for about 2 weeks to about In some embodiments, nicotine addiction or nicotine depen 6 weeks , for about 3 weeks to about 6 weeks , or for about dence treatments include both the regulatory agency - ap 9 weeks to about 12 weeks . In some embodiments , a relapse proved treatments and smoking cessation methods, such as rate is lower for subjects administered the unit dose of vaping and behavioral support . Non - limiting examples of cytisine for at least about 4 weeks compared to subjects behavioral support include behavioral support useful for administered the unit dose of cytisine for at least about 2 reducing, preventing, or otherwise treating anxiety, depres weeks. In other embodiments , a relapse rate is lower for sion , and / or withdrawal symptoms. In certain embodiments, subjects administered the unit dose of cytisine for at least behavioral support includes counseling , diaries, wearable about 6 weeks compared to subjects administered the unit devices, apps , web - based smoking cessation programs, tex dose of cytisine for at least about 4 weeks . In further ting interventions, and combinations thereof. In further embodiments , a relapse rate is lower for subjects adminis embodiments , behavioral support is provided to non - refrac tered the unit dose of cytisine for at least about 8 weeks tory patients, such as control patients ( e.g. , baseline , admin compared to subjects administered the unit dose of cytisine istered a placebo , administered a smoking , vaping, or nico for at least about 4 weeks . In still further embodiments, a tine cessation medication that does not include relapse rate is lower for subjects administered the unit dose cytisinicline ). In some embodiments , the nicotine addiction of cytisine for at least about 12 weeks compared to subjects or nicotine dependence treatments include FDA - approved , administered the unit dose of cytisine for at least about 4 first- line smoking cessation medications such as NRT, weeks . bupropion , and varenicline . Nicotine replacement therapy [ 0114 ] In some embodiments, administration of cytisine to can be in the form of patch , gum , lozenge , spray, and inhaler. the subject resulted in a significantly better nicotine use [ 0110 ] In some embodiments, the subject is a refractory cessation rate ( smoking cessation rate or vaping succession patient who has failed treatment with one or more nicotine rate ), as compared to a subject administered the commercial addiction or nicotine dependence treatments . For example , 1.5 mg per unit dose titration schedule . In some embodi the subject has failed two or more treatments, three or more ments, the unit dose of 3.0 mg of cytisine is administered treatments , four or more treatments, five or more treatments , three times daily for 6 weeks ( e.g. , the first 6 weeks) six or more treatments , seven or more treatments , eight or followed by placebo for 6 weeks ( e.g. , the second six more treatments , nine or more treatments , or ten or more weeks ). In certain embodiments , behavioral support is pro treatments . In some embodiments, the subject is a refractory vided to the subject during at least a portion of the first 6 patient who has failed nicotine addiction or nicotine depen weeks, during at least a portion of the second 6 weeks, dence treatments comprising NRT, administration of bupro before at least a portion of the first 6 weeks, after at least a US 2021/0077475 A1 Mar. 18 , 2021 10 portion of the second 6 weeks , or during a combination 45 % , about 50 % , or more , compared to a subject who has thereof. In some embodiments , the unit dose of 3.0 mg of been administered an NRT , a control subject, placebo con cytisine is administered three times daily for 12 weeks. In trol, and /or baseline ; certain embodiments, behavioral support is provided to the [ 0129 ] ( c ) a reduction in serum and / or plasma cotinine subject during at least a portion of the 12 weeks, before the levels of at least about 5 % , at least about 10 % , at least about 12 weeks , after the 12 weeks, or a combination thereof. 15 % , at least about 20 % , at least about 25 % , at least about Thereafter, in some embodiments the subject exhibits one or 30 % , at least about 35 % , at least about 40 % , at least about more of: 45 % , at least about 50 % , or more , as compared to a subject [ 0115 ] ( a ) a reduction in units of nicotine used per day , who has been administered an NRT, a control subject, such as cigarettes smoked per day or vaping per day, as placebo control, and / or baseline ; compared to a subject who has been administered an NRT, [ 0130 ] ( d ) an increase in quit rate of about 5 % to about a control subject, placebo control, and /or baseline ; 100 % , about 5 % to about 75 % , about 5 % to about 50 % , [ 0116 ] ( b ) a reduction in expired CO levels as compared to about 25 % to about 75 % , about 25 % to about 50 % , about a subject who has been administered an NRT, a control 30 % to about 50 % , about 30 % to about 75 % , about 30 % to subject, placebo control, and / or baseline ; about < 100 % , or about 30 % to about 100 % , as compared to [ 0117 ] ( c ) a reduction in the subject's serum and / or plasma a subject who has been administered an NRT, a control cotinine levels compared to a subject who has been admin subject, placebo control, and / or baseline ; istered an NRT, a control subject, placebo control, and / or [ 0131 ] ( e ) no change, no increase , or a decrease in adverse baseline ; events of about 0 % , about 5 % , about 10 % , about 15 % , about [ 0118 ] ( d ) an increase in quit rate as compared to a subject 20 % , about 25 % , about 30 % , about 35 % , about 40 % , about who has been administered an NRT, a control subject, 45 % , about 50 % , or more compared to a subject who has placebo control, and /or baseline ; been administered an NRT, a control subject, placebo con [ 0119 ] ( e ) no change , no increase , or a decrease in adverse trol, and / or baseline ; events compared to a subject who has been administered an [ 0132 ] ( f) an increase in the subject's odds ratio of about NRT, a control subject, placebo control, and / or baseline ; 0 % , about 5 % , about 10 % , about 15 % , about 20 % , about [ 0120 ] ( f) an increase in the subject's odds ratio as com 25 % , about 30 % , about 35 % , about 40 % , about 45 % , about pared to a subject who has been administered an NRT, a 50 % , or more , compared to a subject who has been admin control subject, placebo control, and / or baseline ; istered an NRT, a control subject, placebo control, and /or [ 0121 ] ( g ) an increase in abstinence compared to a subject baseline ; who has been administered an NRT, a control subject, [ 0133 ] ( g ) an increase in abstinence of about 0 % , about placebo control, and /or baseline ; 5 % , about 10 % , about 15 % , about 20 % , about 25 % , about [ 0122 ] ( h ) a reduction in nicotine cravings and / or tobacco 30 % , about 35 % , about 40 % , about 45 % , about 50 % , or cravings compared to a subject who has been administered more compared to a subject who has been administered an an NRT, a control subject, placebo control, and / or baseline ; NRT, a control subject, placebo control, and /or baseline ; [ 0123 ] ( i ) a reduction of the severity of nicotine with [ 0134 ] ( h ) a reduction in tobacco cravings of about 0 % , drawal symptoms compared to a subject who has been about 5 % , about 10 % , about 15 % , about 20 % , about 25 % , administered an NRT, a control subject, placebo control, about 30 % , about 35 % , about 40 % , about 45 % , about 50 % , and / or baseline ; or more , compared to a subject who has been administered [ 0124 ] ( i) a reduction of the severity of anxiety compared an NRT, a control subject, placebo control, and / or baseline ; to a subject who has been administered an NRT, a control [ 0135 ] ( i ) a reduction of the severity of nicotine with subject, placebo control, and / or baseline ; and / or drawal symptoms of about 0 % , about 5 % , about 10 % , about [ 0125 ] ( k ) a reduction of the severity of depression com 15 % , about 20 % , about 25 % , about 30 % , about 35 % , about pared to a subject who has been administered an NRT, a 40 % , about 45 % , about 50 % , or more , compared to a subject control subject, placebo control, and / or baseline . who has been administered an NRT, a control subject, [ 0126 ] In one embodiment, methods of the present disclo placebo control, and / or baseline ; sure comprise measuring baseline levels of one or more [ 0136 ] ( j) a reduction of the severity of anxiety of about markers set forth in ( a ) - ( k ) above prior to dosing the subject 0 % , about 5 % , about 10 % , about 15 % , about 20 % , about or subject group . In another embodiment, the methods 25 % , about 30 % , about 35 % , about 40 % , about 45 % , about comprise administering a composition as disclosed herein to 50 % , or more compared to a subject who has been admin the subject after baseline levels of one or more markers set istered an NRT, a control subject, placebo control, and /or forth in ( a ) -( k ) are determined , and subsequently taking an baseline ; and /or additional measurement of said one or more markers . In [ 0137 ] ( k ) a reduction of the severity of depression of another embodiment, upon treatment with a composition of about 0 % , about 5 % , about 10 % , about 15 % , about 20 % , the present disclosure, the subject exhibits one or more of: about 25 % , about 30 % , about 35 % , about 40 % , about 45 % , [ 0127 ] ( a ) a reduction in units of nicotine used per day, about 50 % , or more , compared to a subject who has been such as cigarettes smoked per day or vaping per day by at administered an NRT, a control subject, placebo control, least about 10 % , at least about 20 % , at least about 30 % , at and / or baseline . least about 40 % , at least about 50 % , or more , compared to [ 0138 ] In some embodiments, methods of the present a subject who has been administered an NRT , a control disclosure include treating a nicotine addiction , a nicotine subject, placebo control, and / or baseline ; dependence , promoting cessation of smoking and / or vaping , [ 0128 ] ( b ) a reduction in expired CO levels of about 5 % to and / or promoting a reduction in smoking and / or vaping in a about 100 % compared to baseline, control, or placebo subject in need thereof, the method comprising administer levels , for example about 5 % , about 10 % , about 15 % , about ing cytisine provided in a unit dose of 3.0 mg , 1.5 mg , or 1.0 20 % , about 25 % , about 30 % , about 35 % , about 40 % , about mg of cytisine three times daily to the subject. In certain US 2021/0077475 A1 Mar. 18 , 2021 11 embodiments, the subject experiences no adverse events ing cytisine provided in a unit dose of 3.0 mg , 1.5 mg , or 1.0 after receiving the cytisine treatment . In some embodiments, mg of cytisine three times daily to the subject wherein the the adverse event is selected from the group consisting of an subject is a refractory patient who has failed treatment with URTI, abnormal dreams, nausea , insomnia , headache, one or more nicotine addiction , nicotine dependence , or fatigue, and constipation. In certain embodiments , the sub smoking cessation treatments . In some embodiments, the ject experiences no nausea after receiving the cytisine treat nicotine addiction , nicotine dependence , or smoking cessa ment. In some embodiments, cytisine is administered for tion treatments are selected from NRT, administration of about 6 weeks or for about 12 weeks. In some embodiments, bupropion , administration of varenicline , electronic ciga the unit dose of cytisine comprises ( a ) two tablets, each rettes , vaping, and a combination thereof. tablet either containing 1.5 mg or 3.0 mg of cytisine, ( b ) a [ 0143 ] In some embodiments, methods of the present single tablet either containing 1.5 mg or 3.0 mg of cytisine , disclosure include treating a nicotine addiction, a nicotine or ( c ) three tablets, each tablet containing 1.0 mg of cytisine . dependence , promoting cessation of smoking and /or vaping, In some embodiments, the subject is a refractory patient who and / or promoting a reduction in smoking and / or vaping in a has failed treatment with one or more nicotine addiction , subject in need thereof, the method comprising administer nicotine dependence , or smoking cessation treatments . In ing cytisine provided in a unit dose of 3.0 mg , 1.5 mg , or 1.0 some embodiments , the nicotine addiction , nicotine depen mg of cytisine three times daily to the subject wherein the dence, or smoking cessation treatments are selected from subject ( a ) smoked ten or more cigarettes per day prior to the NRT, administration of bupropion , administration of vareni administration of cytisine, ( b ) has expired air CO concen cline , electronic cigarettes, vaping, and a combination tration of about 10 ppm or greater prior to the administration thereof. In some embodiments, the subject ( a ) smoked ten or of cytisine, or ( c ) a combination of ( a ) and ( b ) . more cigarettes or used ten or more vapes per day prior to [ 0144 ] In some embodiments, methods of the present the administration of cytisine , ( b ) has expired air CO con disclosure include treating a nicotine addiction , a nicotine centration of about 10 ppm or greater prior to the adminis dependence, promoting cessation of smoking and /or vaping, tration of cytisine , or ( c ) a combination of ( a ) and ( b ). In and / or promoting a reduction in smoking and / or vaping in a some embodiments , the methods further comprise providing subject in need thereof, the method comprising administer behavioral support to the subject. ing cytisine provided in a unit dose of 3.0 mg , 1.5 mg , or 1.0 [ 0139 ] In some embodiments, methods of the present mg of cytisine three times daily to the subject, and providing disclosure include treating a nicotine addiction , a nicotine behavioral support to the subject. dependence, promoting cessation of smoking and / or vaping, [ 0145 ] Methods of the present disclosure further include and / or promoting a reduction in smoking and / or vaping in a treatment of nicotine addiction or nicotine dependence in a subject in need thereof, the method comprising administer subject in need thereof, the method comprising administer ing cytisine provided in a unit dose of 3.0 mg , 1.5 mg , or 1.0 ing cytisine to the subject, wherein the subject is a refractory mg of cytisine three times daily to the subject wherein the patient who has failed treatment with one or more nicotine subject experiences no adverse events after receiving the addiction or nicotine dependence treatments . In certain cytisine treatment. In some embodiments , the adverse event embodiments, the nicotine addiction or nicotine dependence is selected from the group consisting of an URTI, abnormal treatments comprise NRT, administration of bupropion , dreams, nausea , insomnia, headache , fatigue, and constipa administration of varenicline, electronic cigarettes, vaping, tion . or a combination thereof. In some embodiments , cytisine is [ 0140 ] In some embodiments, methods of the present provided in a unit dose of about 1.0 mg to about 6.0 mg of disclosure include treating a nicotine addiction , a nicotine cytisine three to six times daily to a subject in need thereof. dependence , promoting cessation of smoking and / or vaping, In certain embodiments, cytisine is provided in a unit dose and / or promoting a reduction in smoking and / or vaping in a of 3.0 mg of cytisine three times daily to a subject in need subject in need thereof, the method comprising administer thereof. In some embodiments , the unit dose of cytisine ing cytisine provided in a unit dose of 3.0 mg , 1.5 mg , or 1.0 comprises ( a ) two tablets , each tablet either containing 1.5 mg of cytisine three times daily to the subject wherein the mg or 3.0 mg of cytisine , ( b ) a single tablet either containing subject experiences no nausea after receiving the cytisine 1.5 mg or 3.0 mg of cytisine , or ( c ) three tablets, each tablet treatment. containing 1.0 mg of cytisine . In some embodiments , [ 0141 ] In some embodiments, methods of the present cytisine is administered for about 6 weeks or for about 12 disclosure include treating a nicotine addiction , a nicotine weeks . In some embodiments , the subject experiences no dependence , promoting cessation of smoking and / or vaping, adverse events after receiving the cytisine treatment . In and / or promoting a reduction in smoking and / or vaping in a certain embodiments, the adverse event is selected from the subject in need thereof, the method comprising administer group consisting of an URTI, abnormal dreams, nausea , ing cytisine provided in a unit dose of 3.0 mg , 1.5 mg , or 1.0 insomnia, headache, fatigue, and constipation . In some mg of cytisine three times daily to the subject for about 6 embodiments, the subject ( a ) smoked ten or more cigarettes weeks or for about 12 weeks . In some embodiments , the unit per day prior to the administration of cytisine , ( b ) has dose of cytisine comprises ( a ) two tablets , each tablet either expired air CO concentration of about 10 ppm or greater containing 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet prior to the administration of cytisine, or ( c ) a combination either containing 1.5 mg or 3.0 mg of cytisine , or ( c ) three of ( a ) and ( b ). tablets , each tablet containing 1.0 mg of cytisine. [ 0146 ] Methods of the present disclosure further provide [ 0142 ] In some embodiments, methods of the present methods of preventing smoking and / or vaping relapse in a disclosure include treating a nicotine addiction , a nicotine subject in need thereof, the method comprising administer dependence , promoting cessation of smoking and / or vaping, ing cytisine provided in a unit dose of ( a ) two tablets , each and / or promoting a reduction in smoking and / or vaping in a tablet either containing 1.5 mg or 3.0 mg of cytisine, ( b ) a subject in need thereof, the method comprising administer single tablet either containing 1.5 mg or 3.0 mg of cytisine , US 2021/0077475 A1 Mar. 18 , 2021 12 or ( C ) three tablets, each tablet containing 1.0 mg of cytisine , nicotine addiction , nicotine dependence , or smoking cessa three times daily to the subject. In some embodiments, tion treatments are selected from NRT, administration of cytisine is administered for about 6 weeks or for about 12 bupropion, administration of varenicline, electronic ciga weeks . In some embodiments, the subject experiences no rettes, vaping , and a combination thereof. In some embodi adverse events after receiving the cytisine treatment. In ments , the subject ( a ) smoked ten or more cigarettes per day certain embodiments , the adverse event is selected from the prior to the administration of cytisine, ( b ) has expired air CO group consisting of an URTI, abnormal dreams, nausea , concentration of about 10 ppm or greater prior to the insomnia, headache , fatigue , and constipation . In some administration of cytisine, or ( c ) a combination of ( a ) and embodiments, the subject ( a ) smoked ten or more cigarettes ( b ). In some embodiments, the methods further comprise per day prior to the administration of cytisine, ( b ) has providing behavioral support to the subject. expired air CO concentration of about 10 ppm or greater [ 0149 ] The present disclosure also provides medicaments , prior to the administration of cytisine , or ( c ) a combination such as , a medicament comprising a unit dose of 3.0 mg , 1.5 of ( a ) and ( b ). In some embodiments , the subject is a mg , or 1.0 mg of cytisine for treating a nicotine addiction , refractory patient who has failed treatment with one or more a nicotine dependence , promoting cessation of smoking smoking cessation treatments . In certain embodiments, the and / or vaping, and / or promoting a reduction in smoking smoking cessation treatments comprise NRT, administration and / or vaping in a subject in need thereof, wherein the of bupropion , administration of varenicline , electronic ciga medicament is for three times daily oral administration to rettes , vaping, or a combination thereof. the subject, and wherein the subject experiences no adverse [ 0147 ] Methods of the present disclosure further include events after receiving the cytisine treatment . In certain preventing smoking and / or vaping relapse in a subject in embodiments , the adverse event is selected from the group need thereof, the method comprising administering cytisine consisting of an URTI, abnormal dreams, nausea , insomnia , to the subject, wherein the subject is a refractory patient who headache , fatigue, and constipation . In certain embodiments , has failed treatment with one or more smoking cessation the subject experiences no nausea after receiving the cytisine treatments selected from the group consisting of NRT, treatment. administration of bupropion , administration of varenicline , [ 0150 ] The present disclosure further provides medica electronic cigarettes, vaping , or a combination thereof. In ments, such as , a medicament comprising a unit dose of 3.0 some embodiments , the subject ( a ) smoked ten or more mg , 1.5 mg , or 1.0 mg of cytisine for treating a nicotine cigarettes per day prior to the administration of cytisine, ( b ) addiction, a nicotine dependence, promoting cessation of has expired air CO concentration of about 10 ppm or greater smoking and / or vaping, and / or promoting a reduction in prior to the administration of cytisine , or ( c ) a combination smoking and / or vaping in a subject in need thereof, and of ( a ) and ( b ). In some embodiments , the unit dose of wherein the cytisine is administered for about 6 weeks or for cytisine comprises ( a ) two tablets , each tablet either con about 12 weeks . In some embodiments , the unit dose of taining 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet either cytisine comprises ( a ) two tablets , each tablet either con containing 1.5 mg or 3.0 mg of cytisine, or ( c ) three tablets , taining 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet either each tablet containing 1.0 mg of cytisine , three times daily containing 1.5 mg or 3.0 mg of cytisine , or ( c ) three tablets , to the subject, and wherein cytisine is administered for about each tablet containing 1.0 mg of cytisine . 6 weeks or for about 12 weeks. In some embodiments, the [ 0151 ] In some embodiments, the present disclosure fur subject experiences no adverse events selected from the ther provides a medicament comprising a unit dose of 3.0 group consisting of an URTI, abnormal dreams, nausea , mg , 1.5 mg , or 1.0 mg of cytisine for treating a nicotine insomnia, headache, fatigue, and constipation after receiving addiction , a nicotine dependence, promoting cessation of the cytisine treatment. smoking and / or vaping , and / or promoting a reduction in [ 0148 ] The present disclosure also provides medicaments , smoking and / or vaping in a subject in need thereof, and such as , a medicament comprising a unit dose of 3.0 mg , 1.5 wherein the subject is a refractory patient who has failed mg , or 1.0 mg of cytisine for treating a nicotine addiction , treatment with one or more nicotine addiction or smoking a nicotine dependence, promoting cessation of smoking cessation treatments . In certain embodiments , the nicotine and / or vaping , and / or promoting a reduction in smoking addiction or smoking cessation treatments are selected from and / or vaping in a subject in need thereof, wherein the NRT, administration of bupropion , administration of vareni medicament is for three times daily oral administration to cline , electronic cigarettes, vaping , and a combination the subject. In some embodiments, the subject experiences thereof. no adverse events after receiving the cytisine treatment. In [ 0152 ] In some embodiments, the present disclosure fur certain embodiments , the adverse event is selected from the ther provides a medicament comprising a unit dose of 3.0 group consisting of an URTI, abnormal dreams, nausea , mg , 1.5 mg , or 1.0 mg of cytisine for treating a nicotine insomnia , headache , fatigue , and constipation . In certain addiction , a nicotine dependence, promoting cessation of embodiments, the subject experiences no nausea after smoking and / or vaping, and / or promoting a reduction in receiving the cytisine treatment. In some embodiments, smoking and / or vaping in a subject in need thereof, and cytisine is administered for about 6 weeks or for about 12 wherein the subject ( a ) smoked ten or more cigarettes per weeks. In some embodiments, the unit dose of cytisine day prior to the administration of cytisine , ( b ) has expired air comprises ( a ) two tablets , each tablet either containing 1.5 CO concentration of about 10 ppm or greater prior to the mg or 3.0 mg of cytisine, ( b ) a single tablet either containing administration of cytisine, or ( c ) a combination of ( a ) and 1.5 mg or 3.0 mg of cytisine, or ( c ) three tablets , each tablet ( b ). containing 1.0 mg of cytisine . In some embodiments , the [ 0153 ] The present disclosure further provides medica subject is a refractory patient who has failed treatment with ments, such as , a medicament comprising cytisine for treat one or more nicotine addiction , nicotine dependence, or ing a nicotine addiction or a nicotine dependence in a subject smoking cessation treatments . In certain embodiments , the that is a refractory patient who has failed treatment with one US 2021/0077475 A1 Mar. 18 , 2021 13 or more nicotine addiction or nicotine dependence treat prises ( a ) two tablets , each tablet either containing 1.5 mg or ments , wherein the medicament is for three times daily oral 3.0 mg of cytisine, ( b ) a single tablet either containing 1.5 administration to the subject. In some embodiments, the mg or 3.0 mg of cytisine, or ( c ) three tablets , each tablet nicotine addiction or nicotine dependence treatments com containing 1.0 mg of cytisine , and wherein cytisine is prise NRT, administration of bupropion , administration of administered for about 6 weeks or for about 12 weeks . In varenicline, electronic cigarettes, vaping, or a combination some embodiments, the subject experiences no adverse thereof . In some embodiments, cytisine is provided in a unit events selected from the group consisting of an URTI, dose of about 1.0 mg to about 6.0 mg of cytisine three to six abnormal dreams, nausea , insomnia , headache , fatigue, and times daily to a subject in need thereof. In certain embodi constipation after receiving the cytisine treatment. ments , cytisine is provided in a unit dose of 3.0 mg of [ 0156 ] In some embodiments , the present disclosure pro cytisine three times daily to a subject in need thereof. In vides uses of a unit dose of 3.0 mg , 1.5 mg , or 1.0 mg of some embodiments, the unit dose of cytisine comprises ( a ) cytisine for treating a nicotine addiction , a nicotine depen two tablets, each tablet either containing 1.5 mg or 3.0 mg dence , promoting cessation of smoking and / or vaping , and / of cytisine, ( b ) a single tablet either containing 1.5 mg or 3.0 or promoting a reduction in smoking and / or vaping in a mg of cytisine, or ( c ) three tablets , each tablet containing 1.0 subject in need thereof, wherein the cytisine is for three mg of cytisine . In some embodiments, cytisine is adminis times daily oral administration to the subject. In some tered for about 6 weeks or for about 12 weeks . In some embodiments, the subject experiences no adverse events embodiments, the subject experiences no adverse events after receiving the cytisine treatment. In certain embodi after receiving the cytisine treatment . In certain embodi ments, the adverse event is selected from the group consist ments , the adverse event is selected from the group consist ing of an URTI, abnormal dreams, nausea , insomnia , head ing of an URTI, abnormal dreams, nausea , insomnia , head ache , fatigue, and constipation . In certain embodiments , the ache , fatigue, and constipation . In some embodiments , the subject experiences no nausea after receiving the cytisine subject ( a ) smoked ten or more cigarettes per day prior to the treatment. In some embodiments, cytisine is administered administration of cytisine , ( b ) has expired air CO concen for about 6 weeks or for about 12 weeks. In some embodi tration of about 10 ppm or greater prior to the administration ments , the unit dose of cytisine comprises ( a ) two tablets, of cytisine , or ( c ) a combination of ( a ) and ( b ) . each tablet either containing 1.5 mg or 3.0 mg of cytisine, ( b ) [ 0154 ] In some embodiments , the medicament comprises a single tablet either containing 1.5 mg or 3.0 mg of cytisine, a unit dose of cytisine in ( a ) two tablets , each tablet either or ( C ) three tablets, each tablet containing 1.0 mg of cytisine. containing 1.5 mg or 3.0 mg of cytisine, ( b ) a single tablet In some embodiments, the subject is a refractory patient who either containing 1.5 mg or 3.0 mg of cytisine, or ( c ) three has failed treatment with one or more nicotine addiction , tablets , each tablet containing 1.0 mg of cytisine for pre nicotine dependence, or smoking cessation treatments . In venting smoking and / or vaping relapse in a subject in need certain embodiments, the nicotine addiction, nicotine depen thereof, wherein the medicament is for three times daily oral dence , or smoking cessation treatments are selected from administration to the subject. In certain embodiments , NRT, administration of bupropion , administration of vareni cytisine is administered for about 6 weeks or for about 12 cline , electronic cigarettes, vaping , and a combination weeks . In some embodiments, the subject experiences no thereof . In some embodiments, the subject ( a ) smoked ten or adverse events after receiving the cytisine treatment . In more cigarettes per day prior to the administration of certain embodiments , the adverse event is selected from the cytisine , ( b ) has expired air CO concentration of about 10 group consisting of an URTI, abnormal dreams, nausea , ppm or greater prior to the administration of cytisine, or ( c ) insomnia , headache, fatigue, and constipation . In some a combination of ( a ) and ( b ) . In some embodiments, the uses embodiments, the subject ( a ) smoked ten or more cigarettes further include providing behavioral support to the subject. per day prior to the administration of cytisine, ( b ) has [ 0157 ] The present disclosure further provides uses of expired air CO concentration of about 10 ppm or greater cytisine , such as for treating a nicotine addiction or nicotine prior to the administration of cytisine , or ( c ) a combination dependence in a subject that is a refractory patient who has of ( a ) and ( b ). In some embodiments, the subject is a failed treatment with one or more nicotine addiction or refractory patient who has failed treatment with one or more nicotine dependence treatments, wherein the cytisine is for smoking cessation treatments . In certain embodiments, the three times daily oral administration to the subject. In certain smoking cessation treatments comprise NRT, administration embodiments , the nicotine addiction or nicotine dependence of bupropion , administration of varenicline , electronic ciga treatments comprise NRT, administration of bupropion, rettes, vaping, or a combination thereof. administration of varenicline, electronic cigarettes, vaping, [ 0155 ] The present disclosure further provides medica or a combination thereof. In some embodiments , cytisine is ments, such as , a medicament comprising cytisine for pre provided in a unit dose of about 1.0 mg to about 6.0 mg of venting smoking and / or vaping relapse in a subject that is a cytisine three to six times daily to a subject in need thereof. refractory patient who has failed treatment with one or more In certain embodiments , cytisine is provided in a unit dose nicotine addiction or nicotine dependence treatments of 3.0 mg of cytisine three times daily to a subject in need selected from the group consisting of NRT , administration of thereof. In certain embodiments, the unit dose of cytisine bupropion , administration of varenicline , electronic ciga comprises ( a ) two tablets , each tablet either containing 1.5 rettes, or vaping, wherein the medicament is for three times mg or 3.0 mg of cytisine , ( b ) a single tablet either containing daily oral administration to the subject. In some embodi 1.5 mg or 3.0 mg of cytisine, or ( c ) three tablets, each tablet ments , the subject ( a ) smoked ten or more cigarettes per day containing 1.0 mg of cytisine . In some embodiments , prior to the administration of cytisine , ( b ) has expired air CO cytisine is administered for about 6 weeks or for about 12 concentration of about 10 ppm or greater prior to the weeks. In some embodiments , the subject experiences no administration of cytisine, or ( c ) a combination of ( a ) and adverse events after receiving the cytisine treatment . In ( b ) . In some embodiments , the unit dose of cytisine com certain embodiments, the adverse event is selected from the US 2021/0077475 A1 Mar. 18 , 2021 14 group consisting of an URTI, abnormal dreams, nausea , embodiments, the subject experiences no nausea after insomnia, headache, fatigue, and constipation . In some receiving the cytisine treatment. In some embodiments , embodiments, the subject ( a ) smoked ten or more cigarettes cytisine is administered for about 6 weeks or for about 12 per day prior to the administration of cytisine, ( b ) has weeks. In some embodiments, a unit dose of cytisine com expired air CO concentration of about 10 ppm or greater prises ( a ) two tablets, each tablet either containing 1.5 mg or prior to the administration of cytisine , or ( c ) a combination 3.0 mg of cytisine, ( b ) a single tablet either containing 1.5 of ( a ) and ( b ) . mg or 3.0 mg of cytisine, or ( c ) three tablets , each tablet [ 0158 ] In some embodiments , uses of a unit dose of containing 1.0 mg of cytisine. In some embodiments, the cytisine in the form of ( a ) two tablets , each tablet either subject is a refractory patient who has failed treatment with containing 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet one or more nicotine addiction , nicotine dependence, or either containing 1.5 mg or 3.0 mg of cytisine, or ( c ) three smoking cessation treatments . In certain embodiments , the tablets , each tablet containing 1.0 mg of cytisine include nicotine addiction, nicotine dependence , or smoking cessa preventing smoking relapse in a subject in need thereof, tion treatments are selected from NRT, administration of wherein the cytisine is for three times daily oral adminis bupropion , administration of varenicline , electronic ciga tration to the subject. In some embodiments, cytisine is rettes, vaping , and a combination thereof. In some embodi administered for about 6 weeks or for about 12 weeks . In ments , the subject ( a ) smoked ten or more cigarettes per day some embodiments, the subject experiences no adverse prior to the administration of cytisine, ( b ) has expired air CO events after receiving the cytisine treatment . In certain concentration of about 10 ppm or greater prior to the embodiments, the adverse event is selected from the group administration of cytisine, or ( c ) a combination of ( a ) and consisting of an URTI, abnormal dreams, nausea , insomnia , ( b ). In some embodiments, the uses further comprise pro headache , fatigue, and constipation . In some embodiments, viding behavioral support to the subject. the subject ( a ) smoked ten or more cigarettes per day prior [ 0161 ] In some embodiments, the uses of tablets compris to the administration of cytisine , ( b ) has expired air CO ing about 1.0 mg or 1.5 mg of cytisine are for three times concentration of about 10 ppm or greater prior to the daily oral administration of about 3.0 mg of cytisine to a administration of cytisine, or ( c ) a combination of ( a ) and subject that is a refractory patient who has failed treatment ( b ) . In some embodiments, the subject is a refractory patient with one or more nicotine addiction or nicotine dependence who has failed treatment with one or more smoking cessa treatments to treat a nicotine addiction or nicotine depen tion treatments . In certain embodiments, the smoking ces dence in the subject. In certain embodiments, the nicotine sation treatments comprise NRT, administration of bupro addiction or nicotine dependence treatments comprise NRT, pion , administration of varenicline , electronic cigarettes , administration of bupropion , administration of varenicline , vaping, or a combination thereof. electronic cigarettes, vaping, or a combination thereof. In [ 0159 ] In some embodiments, uses of cytisine for prevent some embodiments, cytisine is provided in a unit dose of ing smoking relapse in a subject that is a refractory patient about 1.0 mg to about 6.0 mg of cytisine three to six times who has failed treatment with one or more nicotine addiction daily to a subject in need thereof. In certain embodiments, or nicotine dependence treatments selected from the group cytisine is provided in a unit dose of 3.0 mg of cytisine three consisting of NRT, administration of bupropion , administra times daily to a subject in need thereof. In some embodi tion of varenicline, electronic cigarettes, or vaping , wherein ments, the unit dose of cytisine comprises ( a ) two tablets , the cytisine is for three times daily oral administration to the each tablet either containing 1.5 mg or 3.0 mg of cytisine, ( b ) subject. In some embodiments, the subject ( a ) smoked ten or a single tablet either containing 1.5 mg or 3.0 mg of cytisine , more cigarettes per day prior to the administration of or ( C ) three tablets, each tablet containing 1.0 mg of cytisine. cytisine , ( b ) has expired air CO concentration of about 10 In some embodiments , cytisine is administered for about 6 ppm or greater prior to the administration of cytisine , or ( c ) weeks or for about 12 weeks . In some embodiments, the a combination of ( a ) and ( b ). In certain embodiments, the subject experiences no adverse events after receiving the unit dose of cytisine comprises ( a ) two tablets , each tablet cytisine treatment. In certain embodiments, the adverse either containing 1.5 mg or 3.0 mg of cytisine, ( b ) a single event is selected from the group consisting of an URTI, tablet either containing 1.5 mg or 3.0 mg of cytisine, or ( c ) abnormal dreams, nausea , insomnia , headache , fatigue, and three tablets , each tablet containing 1.0 mg of cytisine , and constipation . In some embodiments, the subject ( a ) smoked wherein cytisine is administered for about 6 weeks or for ten or more cigarettes per day prior to the administration of about 12 weeks . In some embodiments, the subject experi cytisine, ( b ) has expired air CO concentration of about 10 ences no adverse events selected from the group consisting ppm or greater prior to the administration of cytisine, or ( c ) of an URTI, abnormal dreams, nausea , insomnia , headache , a combination of ( a ) and ( b ). fatigue , and constipation after receiving the cytisine treat [ 0162 ] In some embodiments, the uses of tablets compris ment. ing about 1.0 mg or about 1.5 mg of cytisine are for three [ 0160 ] The present disclosure further provides uses of times daily oral administration of about 3.0 mg of cytisine tablets comprising about 1.0 mg or 1.5 mg of cytisine are for to a subject to prevent smoking and / or vaping relapse in the three times daily oral administration of about 3.0 mg of subject. In certain embodiments , the cytisine is administered cytisine to a subject to treat a nicotine addiction, a nicotine for about 6 weeks or for about 12 weeks. In some embodi dependence , promoting cessation of smoking and / or vaping, ments , the subject experiences no adverse events after and / or promoting a reduction in smoking and / or vaping in receiving the cytisine treatment. In certain embodiments, the the subject. In some embodiments , the subject experiences adverse event is selected from the group consisting of an no adverse events after receiving the cytisine treatment. In URTI, abnormal dreams, nausea , insomnia , headache , certain embodiments, the adverse event is selected from the fatigue , and constipation . In some embodiments, the subject group consisting of an URTI, abnormal dreams, nausea , ( a ) smoked ten or more cigarettes per day prior to the insomnia , headache , fatigue , and constipation . In certain administration of cytisine, ( b ) has expired air CO concen US 2021/0077475 A1 Mar. 18 , 2021 15 tration of about 10 ppm or greater prior to the administration tration of the composition , or after administration of the of cytisine, or ( c ) a combination of ( a ) and ( b ) . In some composition . In some embodiments, the one or more ques embodiments, the subject is a refractory patient who has tionnaires are provided to the subject once , twice, three failed treatment with one or more smoking cessation treat times , four times , five times , six times , seven times , eight ments . In certain embodiments , the smoking cessation treat times , nine times , ten times , 15 times , 20 times , or 30 times . ments comprise NRT, administration of bupropion, admin [ 0167 ] The referenced patents, patent applications, and istration of varenicline, electronic cigarettes, vaping , or a scientific literature referred to herein are hereby incorpo combination thereof. rated by reference in their entirety as if each individual [ 0163 ] In some embodiments, the uses of tablets compris publication, patent, or patent application were specifically ing about 1.0 mg or about 1.5 mg of cytisine are for three and individually indicated to be incorporated by reference . times daily oral administration of about 3.0 mg of cytisine Any conflict between any reference cited herein and the to a subject who has failed treatment with one or more specific teachings of this specification shall be resolved in nicotine addiction or nicotine dependence treatments favor of the latter. Likewise, any conflict between an art selected from the group consisting of NRT, administration of understood definition of a word or phrase and a definition of bupropion , administration of varenicline, electronic ciga the word or phrase as specifically taught in this specification rettes , or vaping to prevent smoking relapse in the subject. shall be resolved in favor of the latter . In some embodiments, the subject ( a ) smoked ten or more [ 0168 ] As can be appreciated from the disclosure above , cigarettes per day prior to the administration of cytisine, ( b ) the present invention has a wide variety of applications . The has expired air CO concentration of about 10 ppm or greater invention is further illustrated by the following examples, prior to the administration of cytisine , or ( c ) a combination which are only illustrative and are not intended to limit the of ( a ) and ( b ). In some embodiments, a unit dose of cytisine definition and scope of the invention in any way. comprises ( a ) two tablets , each tablet either containing 1.5 Example 1 : Impact of Cytisine on Treating mg or 3.0 mg of cytisine, ( b ) a single tablet either containing Nicotine Addiction 1.5 mg or 3.0 mg of cytisine, or ( c ) three tablets, each tablet [ 0169 ] This was a six - arm , multi - center, double -blind , containing 1.0 mg of cytisine , and wherein cytisine is randomized, placebo - controlled study conducted in male or administered for about 6 weeks or for about 12 weeks . In female adults years of age , smoking 10+ cigarettes daily, and some embodiments, the subject experiences no adverse willing to set a quit date that is 5-7 days after randomization . events selected from the group consisting of an URTI, This study was designed to evaluate the effectiveness of 1.5 abnormal dreams, nausea , insomnia , headache, fatigue, and mg of cytisine versus placebo using the commercial titration constipation after receiving the cytisine treatment. schedule approved in Central and Eastern Europe. The study [ 0164 ] Thus, in yet another aspect , provided herein is a also evaluated the effectiveness of a simplified TID dosing method of treating of nicotine addiction or nicotine depen schedule for 1.5 mg and an increased dose of 3.0 mg ( using dence in a subject, comprising administering cytisine to a both the commercial titration ( COM ) and simplified TID subject in need thereof, wherein the subject is a refractory dosing schedules ). The overall goal of the study was to patient who has failed treatment with one or more nicotine obtain estimates of effect size for efficacy and safety end addiction or nicotine dependence treatments . Suitable unit points that will be used to inform the design of future Phase doses include doses between about 1.0 mg and about 6 mg 3 studies . which can be administered three to six times daily, for [ 0170 ] The dosing schedules for the study are shown in example , at about equal intervals . For example, in some FIG . 1. The study was double - blinded to dose but not to the embodiments , the methods comprise administering cytisine administration schedule, and the study arms were as shown provided in a unit dose of 3.0 mg of cytisine three times in FIG . 2. Study treatment started the day after randomiza daily to a refractory patient. Any suitable duration of admin tion such that study treatment was initiated prior to the quit istration can be used in the methods disclosed herein , for date , as shown in FIG . 3 . example , about 26 weeks , about 12 weeks , or about 6 weeks . [ 0171 ] The primary efficacy endpoint for this study was In some embodiments , the treatment is administered for the percent reduction in the number of cigarettes smoked about 6 weeks . during treatment, which was calculated as follows : [ 0165 ] In some embodiments , the methods disclosed herein can further comprise providing behavioral support to N the subject, for example, a refractory patient. Behavioral 100 support can include counseling which can further include, [ BXD * 100 % but is not limited to , the following topics : abstinence , past quit experience, anticipate triggers or challenges in the where N = total number of cigarettes smoked , B = number of upcoming attempt, alcohol use , proximity to and frequency cigarettes smoked at baseline and D = number of days. around other nicotine users ( e.g. , smokers , vapers ), recog [ 0172 ] The secondary efficacy endpoint was the quit rate nition of dangerous situations, and development of coping ( confirmed by CO < 10 ppm ) and included an analysis at skills . week 4 ( i.e. , the end of treatment) and sustained ( 4 - week ) [ 0166 ] In some embodiments, the methods disclosed abstinence from Week 5 to Week 8 ( i.e. , off treatment) . herein can further comprise providing one or more ques [ 0173 ] The subject demographics are summarized in FIG . tionnaires to the subject. Non - limiting examples of the one or more questionnaires include an E -cigarette Dependence 4. The cigarettes subject's smoked before and after treatment Scale questionnaire, a marijuana craving questionnaire - short are shown in FIG . 5 . form , the Fagerström Test for Nicotine Dependence, the 1.1 Results Smoking Self -Efficacy questionnaire (SEQ - 12 ), the Brief [ 0174 ] Table 1 summarizes the demographics of the sub Questionnaire of Smoking Urges ( QSU - Brief) question jects . In total , 254 male or female adults 218 years of age naire , the Minnesota Nicotine Withdrawal Scale ( MNWS ) who smoked 210 cigarettes daily and were willing to set a questionnaire , the “ Since Last Visit ” C - SSRS questionnaire , quit date 5 to 7 days after randomization were enrolled in the and the HADS questionnaire . In certain embodiments, the study. Demographics and baseline characteristics were gen questionnaire ( s ) can be provided to the subject at any time erally well balanced across both schedules and treatment during administration of the composition , before adminis arms. US 2021/0077475 A1 Mar. 18 , 2021 16

TABLE 1 Subject Demographics

Downward Titration TID 1.5 mg 3.0 mg 1.5 mg 3.0 mg Placebo ALL ( n = 51 ) ( n = 50 ) ( n = 52 ) ( n = 50 ) ( n = 51 ) ( n = 254 ) Sex Male 23 (45 % ) 30 ( 60 %) 23 ( 44 % ) 25 ( 50 % ) 20 ( 39 % ) 121 ( 47 % ) Female 28 ( 55 % ) 20 ( 40 % ) 29 ( 56 % ) 25 ( 50 % ) 31 ( 61 % ) 133 ( 53 % ) Race White 43 ( 84 % ) 40 ( 80 % ) 37 ( 71 % ) 41 ( 82 % ) 39 ( 76 % ) 200 ( 80 % ) Black 7 ( 14 % ) 9 ( 18 %) 13 (25 % ) 7 ( 14 % ) 10 ( 20 %) 46 ( 18% ) Asian 0 0 1 ( 2 % ) 1 ( 2% ) 1 (2 %) 3 ( 1 % ) Pacific 0 0 0 0 0 0 Native 0 1 (2 % ) 1 (2 %) 0 0 3 ( 1 % ) Other 1 ( 2 % ) 0 0 1 ( 2 % ) 1 (2 % ) 3 ( 1 %) Age (mean years) 49.8 50.0 47.0 46.3 48.9 48.4 Weight (mean kg ) 82.1 83.0 80.7 79.5 80.2 81.1 BMI (mean kg /m² ) 27.6 27.8 27.9 27.1 27.9 27.7

[ 0175 ] Of the study population, 53 % percent were female attempts , 35 % of the subjects had previously received and 47 % male . 79 % of the study population was white , with varenicline, 16 % of the subject had bupropion, and 48 % of 18 % black and 3 % of another race . Smoking diary compli the subjects an NRT. TABLE 2 Subject Smoking History

Downward Titration TID

1.5 mg 3.0 mg 1.5 mg 3.0 mg Placebo ALL ( n = 51 ) ( n = 50 ) ( n = 52 ) ( n = 50 ) ( n = 51 ) ( n = 254 ) Smoking duration 33.3 33.2 30.9 30.0 33.0 32.1 (mean years) Daily smoking 20 20 20 18 20 20 (median cigarettes ) Prev quit attempts 5.4 3.8 4.7 3.8 4.9 4.5 ( mean ) Previous treatments

Chantix ® 21 (41 % ) 13 ( 26 % ) 21 (40 % ) 18 ( 36 % ) 19 (37 % ) 92 (36 % ) Zyban ® 9 ( 18 % ) 3 ( 6 % ) 9 ( 17 % ) 7 ( 14 % ) 12 ( 24 % ) 40 ( 16 % ) NRT gum 20 ( 39 % ) 12 ( 24 %) 20 ( 38 % ) 16 ( 32 % ) 24 ( 47 % ) 92 ( 36 % ) NRT patch 23 (45 % ) 19 ( 38 % ) 27 (52 %) 25 ( 50 %) 28 ( 55 % ) 122 ( 48 % ) e - cigarettes/ vaping 15 ( 29 % ) 11 ( 22 % ) 19 ( 36 %) 13 ( 26 %) 18 (35 %) 76 ( 30 % ) ance , on which the primary analysis was based in part, was Analyses from the international EAGLES trial provided high for all treatment arms . Study drug compliance was clear evidence that smoking at a young age and being of U.S. > 94 % for all treatment arms with slightly higher compliance origin was associated with lower success rates for quitting . with the TID schedule ( > 98 % ) . The mean treatment duration The lower success rate in U.S. smokers supports the view was 23.4 days and 96.6 % of the subjects received the mean that smokers in the U.S. may have reached a point in the tobacco epidemic such that those who continue to smoke , doses of cytisine. despite strong cultural pressures not to , have particular [ 0176 ] Table 2 summarizes the smoking history of the characteristics that make it more difficult for them to stop subjects in all treatment arms . Overall, the study population smoking. represented highly addictive smokers who on average were [ 0177 ] Overall, study drug compliance was high for all 48.4 years old and had been smoking for 32 years , meaning treatment arms with the TID schedule better ( 98.18 % ) than that most of them had started smoking in their adolescent the commercial schedule ( 94.90 % ) . More specifically , Table years . In addition , they had an average of 4.5 prior quit 3 summarizes the study drug compliance in all treatment attempts with the last quit attempt approximately 3.7 years arms. Study drug compliance ranged from 96.7 % to 99.5 % prior to entering the study and were currently smoking on in the TID arms while study drug compliance ranged from average a pack of cigarettes a day . Of the previous quit 94.2 % to 96.4 % in the COM arms. US 2021/0077475 A1 Mar. 18 , 2021 17

TABLE 3 Study Drug Compliance Downward Titration Schedule TID Schedule 1.5 mg 3.0 mg Placebo 1.5 mg 3.0 mg Placebo N = 51 N = 50 N = 25 N = 52 N = 52 N = 26 Treatment Duration 23.8 ( 4.76 ) 23.5 ( 4.49 ) 23.9 ( 4.06 ) 25.0 ( 0.14 ) 24.9 ( 0.72 ) 24.3 ( 3.53 ) Mean Days ( std ) Percent of Doses 5.1 ( 18.1 ) 5.8 ( 15.8 ) 3.6 ( 13.7 ) 0.5 ( 1.2 ) 2.4 ( 7.7 ) 3.3 ( 13.6 ) Missed Mean % ( std ) Compliance * 94.9 % 94.2 % 96.4 % 99.5 % 97.6 % 96.7 % 100 % 33 ( 64.7 % ) 32 ( 64.0 % ) 20 ( 88.0 % ) 42 ( 80.8 % ) 37 ( 74.0 % ) 20 ( 76.9 % ) 90 % - < 100 % 13 ( 25.5 % ) 12 ( 24.0 % ) 3 ( 12.0 % ) 10 ( 19.2 % ) 10 ( 20.0 % ) 5 ( 19.2 % ) 80 % - < 90 % 3 ( 5.9 % ) 1 (2.0 % ) 3 (5.9 % ) 0 1 (2.0 %) 1 ( 3.8 % ) < 80 % 2 ( 3.9 % ) 5 ( 10.0 %) 2 ( 3.9 %) 0 2 (4.0 % ) * Defined as [ ( # doses prescribed – # missed doses ) / # doses prescribed ] x 100 . [ 0178 ] The reduction in cigarettes smoked in all treatment a 75 % to 68 % reduction in cigarettes smoking ) . Conversely , arms is shown in FIG . 6 and summarized in Table 4. Results in the placebo -treated arms, the reported reductions in the from the primary analyses demonstrated a significant reduc number of cigarettes smoked ( e.g. , 41 % as the Cigarette tion in percentage of expected cigarettes smoked ( Cigarette Score , representing a 59 % reduction in cigarettes smoked ) Score ) in both COM arms. When pooling the placebo arms, was not paralleled by a corresponding reduction in CO at the Cigarette Score was significantly reduced in both COM only 29 % . A similar pattern for plasma cotinine levels was arms, the 1.5 mg TID arm , and approached significance in observed with far greater reductions in cotinine levels in the the 3.0 mg TID arm . Subjects treated with 1.5 mg or 3.0 mg cytisine arms compared to placebo arms. of cytisine using the COM schedule smoked approximately [ 0181 ] The changes in these objective markers suggest 14 % to 16 % fewer cigarettes than expected versus placebo . that, in general, placebo - treated subjects over - reported their Subjects treated with 1.5 mg or 3.0 mg of cytisine on the TID reduction in cigarettes smoked . It also suggests that the real schedule smoked approximately 9 % to 12 % fewer cigarettes differences in Cigarette Scores between subjects treated with than expected versus the placebo arm . cytisine and those treated with placebo were greater than those actually observed . TABLE 4 [ 0182 ] The quit rates for arms of the TID schedule versus placebo is shown in FIGS . 7 and 8 and summarized in Table Reduction of Cigarettes Smoked and CO 5. Results for the initial quit rate at Week 4 demonstrated Reduction in Reduction both arms of the TID schedule had high odds of success of cigarettes smoked p - value in CO quitting smoking compared with placebo ; subjects in the 3.0 mg of cytisine arm had the best odds of success for quitting Titration smoking : OR : 6.31 ( 95 % CI : 2.28 , 18.45 ) . The OR for the 1.5 80 % 0.001 78 % 1.5 mg of cytisine arm on the TID schedule was 5.81 ( 95 % 3.0 78 % 0.003 71 % CI : 2.12 , 16.87 ) . On the COM schedule , the ORs for the 1.5 Placebo 62 % 40 % and 3.0 mg of cytisine arms were 5.59 ( 95 % CI : 2.03 , 16.29 ) TID and 5.38 ( 95 % CI : 1.95 , 15.72 ) , respectively. 1.5 79 % 0.009 71 % 3.0 74 % 0.052 80 % TABLE 5 Placebo 62 % 29 % Quit Rates - Cytisinicline versus Placebo [ 0179 ] Although the decreases on the TID schedule were End - of - Treatment Continuous Abstinence not as high as those seen on the COM schedule , it should be Week 4 Weeks 5 to 8 noted that subjects in the placebo arm on the TID schedule reported a higher reduction in cigarettes smoked than sub Quit Rate p - value Quit Rate p - value jects in the placebo arm on the COM schedule . The TID Titration placebo subjects smoked only one - third as many cigarettes 1.5 51 % < 0.001 22 % 0.09 as they normally would ( LS mean : 35.30 % ) versus the COM 3.0 50 % < 0.001 16 % 0.23 placebo subjects at one -half as many cigarettes smoked ( LS Placebo 16 % 8 % mean : 47.10 % ) , which possibly masked the cytisine treat TID ment effect on the TID schedule . 1.5 52 % < 0.001 27 % 0.018 [ 0180 ] Expired CO levels were also measured during this 3.0 54 % < 0.001 30 % 0.005 study as an objective biochemical marker for reduction in Placebo 15 % 8 % smoking. The reduction in CO in all treatment arms is shown in FIG . 6 and summarized in Table 4. In all cytisine -treated [ 0183 ] Referring to FIGS . 7 and 8 and Table 5 , for the arms, the reduction in CO ( 55 % to 62 % reduction ) was prolonged abstinence from Week 5 to Week 8 endpoint, both consistent with the reported reduction in cigarettes smoked arms of the TID schedule had higher odds of success for ( e.g. , a range of 25 % to 32 % as Cigarette Scores represents abstinence compared with placebo ; subjects in the 3.0 mg of US 2021/0077475 A1 Mar. 18 , 2021 18 cytisine arm had the best odds of success for abstinence from [ 0191 ] An EMA fits a statistical model to the data . The Weeks 5 to 8 , with an OR of 5.04 ( 95 % CI : 1.42 , 22.32 ) . The EMA model has interaction terms for detecting the existence OR for the 1.5 mg of cytisine arm on the TID schedule was of arm effect differences across discrete factor values . Het 4.33 ( 95 % CI : 1.21 , 19.30 ) . On the COM schedule , the ORs erogeneity of effect estimates is detected when interaction for the 1.5 mg of cytisine and 3.0 mg arms were 3.23 ( 95 % terms materially improve the fit of the model over the model CI : 0.86 , 14.85 ) and 2.24 ( 95 % CI : 0.55 , 10.82 ) , respec without interaction terms. The improvement of fit due to tively . interaction terms is measured by an interaction P value , [ 0184 ] Table 6 summarizes a comparison of the reduction where a small P value , usually less than 0.10 , indicates in expired CO levels and quit rates at Week 4 and Weeks 5 improvement of fit. to 8 for the 3.0 mg of cytisine arm versus placebo . [ 0192 ] There are two types of interactions : qualitative and quantitative. A quantitative interaction exists when the direc TABLE 6 tions of the arm effect estimates are the same for all discrete values of the factor. A qualitative interaction exists when the Reduction in CO and Quit Rates for 3 mg TID versus Placebo direction of effects is mixed for values of the factor . 3.0 mg [ 0193 ] The results from the multiple EMAs performed in CYT Placebo this study are displayed compactly as forest graphs, showing Characteristic ( N = 50 ) ( N = 51 ) P Value for each factor value the subset - related frequencies (distri Reduction in 80 % 38 % p = 0.003 bution between arms) , effect estimate , and applicable con expired CO fidence interval. The EMA forest graphs provide a gestalt Week 4 54 % 16 % p < 0.001 concerning the stability of the overall effect estimate for the Abstinence factors included in the graph . Complete EMA forest graphs Continuous Abstinence 30 % 8 % p = 0.005 also show for each factor the quantitative assessment of ( Weeks 5-8 ) heterogeneity from the EMA model , for example, the inter action P value . Also , arm effect estimates and confidence [ 0185 ] Subjects in the cytisine arms on the TID schedule intervals for each value of the factors are displayed in the also had higher odds of smoking abstinence at the Weeks 6 , forest graphs. ( Such forest graphs appear subsequently .) 7 , and 8 timepoints compared with subjects in the corre [ 0194 ] Justification for Pooling Control Arms sponding arms on the COM schedule versus placebo , as [ 0195 ] The between -arm comparisons were the pairwise demonstrated by higher ORs at each timepoint. comparisons of each active arm to the pooled placebo arm . The justification for comparing to the pooled placebo was 1.2 Sensitivity Objectives and General Methods based on : [ 0186 ] The primary outcome ( Cigarette Score ) and the [ 0196 ] The absence of evidence that the two placebo main secondary abstinence outcomes were subjected to arms differed with respect to the primary or the two sensitivity analyses. The main secondary abstinence out secondary outcomes with P values 0.1197 , 0.9963 , and comes were the initial quit rate at Week 4 and continued 0.9996 , respectively, for the stratified between -control 4 - week abstinence through Week 5 to Week 8 , confirmed by arm comparisons of the Cigarette Score , initial quit expired CO of < 10 ppm designated as Cess / W5-8 / CO Suc success at Week 4 , and Cess / W5-8 / CO success out cess . The objective was to assess the robustness of the comes . findings from the trial, and to perform alternative analyses [ 0197 ] The absence of evidence that the randomization that might either confirm the observed results or challenge between the placebo arms differed with respect to any the conclusions of the trial. of the baseline attributes used as factors in the subse [ 0187 ] Other outcomes related to objective biochemical quently presented EMAs , including clinical site . assessments were also analyzed . The associations between [ 0198 ] For the purposes of sensitivity assessment, this these biochemical assessments are particularly important absence of evidence of placebo arm differences is regarded when used as part of the definition of smoking cessation and as justification for pooling, with the benefit of increased abstinence but are also important because of absence of statistical sensitivity. assessment subjectivity . [ 0199 ] Descriptive Graphs for Daily Reported Mean Ciga [ 0188 ] The focus of these sensitivity analyses in this report rettes is on the comparison of the 3.0 mg of cytisine TID arm to [ 0200 ] Longitudinal graphs for the mean of the number of the pooled placebo ( 0 mg of cytisine ) arm . Some analyses cigarettes reported in the diaries for each study treatment will show the other comparisons for contrast . day ( Days 1-25 following randomization ) are presented [ 0189 ] Effect of Modification Analysis Methodology below . Each arm and the pooled placebo arm are shown in [ 0190 ] A common method for assessing robustness, con a different color or dashed versus solid lines . FIG . 5 illus sistency, and meaning of results from a trial is to perform trates that at each day, subjects did reduce their daily number Effect Modifier Analyses ( EMAS) . The goal of an EMA is to of cigarettes smoked in an attempt to quit by the planned quit evaluate the degree to which arm effects estimated for interval ( Days 5-7 ) with abstinence by Day 8 . discrete values of a baseline attribute differ. For example, an EMA of sex estimates sex - specific arm effects and evaluates 1.3 Biochemical Verification Analysis whether these estimates differ . If a baseline attribute to be [ 0201 ] Following are two longitudinal graphs of the visit evaluated using EMA is not discrete , the attribute is made means and 95 % confidence intervals of CO and cotinine , discrete by specifying cutpoints based on external criteria or respectively, by the pooled placebo arm and cytisine - treated by using percentiles computed from the pooled data (me arms. dian , tertiles, or quartiles ). For example, baseline CO levels [ 0202 ] CO levels ( ppm ) were assessed during the study at split at below 10 ppm or not or using pooled quartile values . screening , baseline , end of study treatment intervention US 2021/0077475 A1 Mar. 18 , 2021 19

( Week 4 ) , and weekly through Week 8 ( FIG . 9 ) . The between TID O mg and TID 3.0 ) as a factor of the percentage screening and baseline visits ’ CO means were approxi of expected cigarettes smoked ( Cigarette Score ). mately equal for all arms. At Week 4 , significant reductions [ 0211 ] FIG . 16 and FIG . 17 are additional assessments for in CO levels for all subjects treated in cytisine -treated arms, BMI and baseline mean number of cigarettes interactions regardless of schedule, were observed . During the follow - up specifically for the 3.0 mg TID arm compared to the pooled period ( with only behavioral support) from Week 4 through placebo arm . Week 8 , the CO means in the pooled placebo arm were [ 0212 ] For BMI , this assessment for the existence of an interaction with arm was evaluated as an EMA using BMI as approximately constant, although somewhat lower than the the factor, where the size of the interaction P would be means before the start of study treatment intervention . The informative of the existence of this interaction ( FIG . 16 ) . means for the active treatment arms remained distinctly The EMA interaction P value for BMI was 0.1303 , not small lower compared to the pooled placebo arm for all follow - up enough to induce concern , but based on the stratum -specific visits , although the means showed a slight upward trend . effect size estimates there was a suggestion of possibly more [ 0203 ] Serum cotinine levels were exploratory and efficacy for high BMI patients as compared to lower BMI assessed only at screening , Week 4 , and Week 8. Reported subjects . results for cotinine of < 10 ng /mL were transformed to 0 [ 0213 ] Evidence of an interaction between arm and the ng /mL prior to statistical analysis. The cotinine graph in baseline mean number of cigarettes ( model covariate ) was FIG . 10 showed the same pattern as observed for CO . All assessed by the parallelism between the arms of the straight subjects in cytisine - treated arms had a material reduction in line relationships between the Cigarette Score and the base cotinine levels at Week 4 and showed a slight upward trend line mean number of cigarettes. The P value for this assess by Week 8 . ment of parallelism as shown in the scatter graph ( FIG . 17 ) was 0.2754 , providing no evidence of the absence of par 1.4 Cigarette Score Analysis allelism . [ 0214 ) Alternative Cigarette Score Analyses [ 0204 ] Primary Model Stratification and Covariate [ 0215 ] The primary outcome was based on the number of Assumptions cigarettes smoked on each day from a diary . The Cigarette [ 0205 ] The primary model of Cigarette Score included Score used the diary data for the planned 25 days while on study treatment . Presented are sensitivity analyses for the covariates for the BMI stratification ( 3 levels ) and the mean comparison of the 3.0 mg TID arm and the pooled placebo number of cigarettes reported by screening diary . The valid arm related to variations on the primary analysis of Cigarette ity of the conclusions from the results of the primary model Score . The alternative definition of the Cigarette Score depended on there being no interaction between each of featured cigarettes recorded in the diary after the planned these covariates and the arm variable . If one or both of these quit period of Days 5-7 , that is , from Day 8 onward , instead interactions were material in the statistical model , then the of from Day 1 onward . magnitude of the estimated arm effect would be a function [ 0216 ] Another alterative analysis was based on re -analy of BMI class and / or the mean number of cigarettes reported ses of the primary Cigarette Score and the above alternative by screening diary. Cigarette Score, with a weight related to the standard error [ 0206 ] The planned statistical analyses of the primary of the mean number of cigarettes estimated from the diary endpoint were performed and , as part of those analyses, each entries . The weight used for each subject was 1 / ( SE ) ?, where SE is the standard error of the mean estimate , and this type of the cytisine treatment arms was compared to the Pooled of weighting, referred to as inverse variance weighting, is Placebo arm on the primary efficacy endpoint ( Cigarette used commonly . This weighting gives greater weight to Score ) . These analyses were performed using analysis of means that are estimated with a smaller SE . A small modi variance models with fixed effects of treatment arm and BMI fication to this definition of weight was necessary , however . ( 18.5 to < 25 kg /m² ; 25 to < 30 kg /m² ; 30 to < 35 kg /m² ) and In computing 1 / ( SE ) ” , a specific rule was used when SE = 0 , a covariate of baseline cigarettes. The analysis used a BMI specifically when all diary entry values were equal. In these variable derived from the subjects ' actual BMI and omitted cases, the SE was computed as if one and only one of the one subject ( 104-144 ) because the subject's BMI ( 39.9 recorded values was larger by one . It can be shown that kg /m² ) was greater than the upper limit of the top BMI when this modification to the data is made SE = 1 / N , where category ( 30 to 35 kg /m² ) . N is the number of the subjects daily ( days ) entries . [ 0217 ] Table 7 shows the P values and effect estimates [ 0207 ] Two variations on this analysis were performed as with 95 % confidence interval for the four analyses described part of the sensitivity analyses . These were: for the comparison of the 3.0 mg TID arm to the pooled [ 0208 ] A model that used a BMI variable derived from placebo arm . When the diary data start was Day 8 instead of the subject's actual BMI , but that included all 254 Day 1 , the effect estimate is somewhat more favorable subjects in the All Randomized Set . The BMI catego ( -11.8 versus -9.5 , respectively, for the primary Cigarette ries used in this analysis were 18.5 to < 25 kg /m² ; 25 to Score ) because smoking data prior to the planned quit day were excluded . For the analyses where weighting was < 30 kg /m² ; 30 to < 35 kg /m² , and 35 kg /m² . applied to the primary Cigarette Score , the effect estimate P [ 0209 ] A model that used the BMI stratification variable value was 0.0466 compared to 0.0675 for the unweighted at randomization . Subject 104-144 was included in this analysis of the primary Cigarette Score. This was because analysis, within the BMI stratum reported for that diary data prior to the planned quit day ( prior to Day 8 ) subject at randomization ( 30 to < 35 kg /m² ) . Conse followed by quitting resulted in larger SEs , thereby decreas quently , this analysis included all 254 subjects in the ing the weight for quitters . This decrease in weighting does All Randomized Set . The BMI categories used in this not apply to the re - defined Cigarette Score using diary data analysis were 18.5 to 25 kg/ m ; 25 to 30 kg/ m ; and starting at Day 8 , and therefore the weighted effect size of 30 to < 35 kg/ m2 the re -defined Cigarette Score was distinctly more favorable [ 0210 ] FIGS . 11A - 11B show a comparison between than compared to the unweighted primary Cigarette Score homogeneity of each group ( COM 0 mg and TID 0 mg , and starting on Day 1 ( -15.0 versus -9.5 , respectively ). US 2021/0077475 A1 Mar. 18 , 2021 20

TABLE 7 P Values and Effective Estimates P value ( 3.0 Weighted mg TID versus Effect estimate analysis Diary start day of outcome Cigarette Score pooled ( 95 % confidence as defined analyzed placebo ) interval ) No Start of intervention (primary outcome ) 0.0466 -9.5 ( -18.8 , -0.2 ) Quit Day ( 8th day after start of intervention ) 0.0326 -11.8 ( -22.5 , -1.0 ) Yes Start of Intervention 0.0675 -11.8 ( -24.4 , 0.9 ) Quit Day ( 8th day after start of intervention ) 0.0006 -15.0 (-23.3 , -6.7 )

[ 0218 ] The analysis of whether there was evidence of TABLE 8 - continued effect heterogeneity across the 8 clinical sites ( subject sources ) was done as an EMA where the interaction P value provided a measure of heterogeneity of effect . This analysis Study Details for Comparing Cytisinicline and Chantix® was done for both the Cigarette Score primary outcome variable and Cess / W5-8 / CO Success . For the Cigarette ORCA - 1 Chantix ® Score , the EMA model has additional covariates for BMI stratification and the mean number of cigarettes reported by screening diary. For Cess / W5-8 / CO Success , no covariates 8 Weeks Sustained quit ( EAGLES ) were added to the EMA model due to the likelihood of ( 4 weeks after treatment) empty cells in the cross classification over the discrete variables of binary outcome, arm , and clinical sites . For example , there were situations where a specific clinical site [ 0221 ] FIG . 13 shows the CO confirmed quit rates had no subjects with success in one or both arms . between 3.0 mg of cytisinicline and 3.0 mg of Chantix® at [ 0219 ] FIGS . 18-25 provide EMA analysis results for each 4 weeks and at 12 weeks of treatment. Chantix® data is of the four comparisons of active cytisine arms to the pooled 7 -day point prevalence , whereas cytisinicline is 1 -day point placebo arm , and for both outcome variables . No evidence prevalence . The CO - confirmed end of treatment quit rate for of effect heterogeneity due to clinical site was found from subjects treated with 3.0 mg of cytisinicline exceeded that of any of these EMAS, that is , the interaction P values are not subjects treated with 3.0 mg of Chantix® at both Week 4 and small enough to induce concern regarding clinical site Week 12 ( end of Chantix® treatment ). Cytisinicline had a heterogeneity . greater efficacy compared to Chantix® . 1.5 Comparison of Quit Rates for Cytisinicline and [ 0222 ] FIG . 14 and Tables 9-11 show the odds ratio of Chantix® cytisinicline and Chantix® at 4 weeks , end of treatment, and [ 0220 ] FIG . 12 and Table 8 show the study design for 4 weeks off treatment . Cytisinicline and Chantix® have comparing cytisinicline ( cytisine) and Chantix® . The treat similar odd ratios and efficacy. While the 95 % CI of both ment duration of Chantix® ( 12 weeks ) was approximately treatments overlap, the odd ratios of the cytisinicline treat 3.5 times longer than that of cytisinicline ( 25 days ). The ment are consistently better than that of Chantix® . sustained abstinence timepoint of Chantix® ( 12 weeks mea sured over last 4 week on treatment) was longer than the that TABLE 9 of cytisinicline ( 8 weeks measured over 4 weeks after end of treatment) . Table 8 includes additional details regarding Odd Ratios of Cytisinicline and Chantix ® at End of Treatment trials with cytisinicline and Chantix® . Cytisinicline Placebo Chantix ® Placebo Quit Rate 54.0 % 15.7 % 38.0 % 13.7 % TABLE 8 Drug -placebo difference 38.3 % 24.3 % Study Details for Comparing Cytisinicline and Chantix ® OR 6.3 4.0 Lower C1,5 % 2.47 3.20 ORCA - 1 Chantix ® Upper C1,5 % 16.11 5.0 Number of subjects 1.5 mg titration 51 EAGLES 3.0 mg titration 50 Chantix ® 1005 1.5 mg TID 52 Placebo 1009 TABLE 10 3.0 mg TID 50 ONCKEN Placebo 51 Chantix ® 130 Odd Ratios of Cytisinicline and Chantix® at 4 Weeks Treatment Placebo 129 Duration of Treatment 25 Days 12 weeks Cytisinicline Placebo Chantix ® Placebo Frequent doctor visits & ? Quit Rate 54.0 % 15.7 % 37.7 % 16.3 % Behavioral support Biochemical confirmation Exhaled CO Exhaled CO Drug -placebo difference 38.3 % 21.4 % Quit Rates OR 6.3 3.1 Lower CI95 % 2.47 1.73 4 Weeks ? ( ONCKEN ) Upper C1,5 % 16.11 5.99 End of Treatment 4 weeks 12 weeks ( EAGLES) US 2021/0077475 A1 Mar. 18 , 2021 21

TABLE 11 [ 0228 ] Effect Modification Analysis of History for Anti smoking Interventions Odd Ratios of Cytisinicline and Chantix ® [ 0229 ] Prior anti - smoking intervention factors were ana at 4 Weeks Off Treatment lyzed for the Cigarette Score primary outcome variable and Cytisinicline Placebo Chantix ® Placebo Cess / W5-8 / CO Success comparing the cytisine 3.0 mg TID Quit Rate 30.0 % 7.8 % 33.2 % 12.5 % arm to the pooled placebo arm ( FIGS . 28 and 29 ) . The Drug -placebo difference 22.2 % 20.7 % factors analyzed include : whether more than 2 anti - smoking OR 5.0 3.5 intervention attempts, and if ever treated or recently treated Lower CI95 % 1.54 2.78 with any of Chantix® , Zyban® , vaping, or nicotine replace Upper Cl95 % 16.50 4.38 ment therapy. The same EMA models used for analyzing clinical sites were performed . The forest graphs for these analyses follow . [ 0223 ] Table 12 shows a recent EAGLES study published [ 0230 ] The only interaction P value of note was that for in 2018 comparing quit rates in the U.S. compared to history of prior use of Chantix® ( “ Chantix® Hx ” ) for the non - U.S . regions. This study notes significantly lower quit Cigarette Score , with P = 0.0508 . However, the interaction P rates in the U.S. versus non - U.S . regions . The overall quit value for the factor variable indicating Chantix® as the most rate of 22 % at 24 weeks for subjects treated with Chantix® recent intervention ( “ Chantix® Most Recent " ) did not indi was only 16 % for U.S. patients ( N = 1065 ) . The quit rates are cate concern ( P = 0.3179 ) . Since the interaction appeared to significantly lower than previous trials with Chantix® that be quantitative and the finding for most recent use was were all U.S. - based . The 24 -week quit rates in the EAGLES discordant, the concern for Chantix® being an effect modi study were lower than 52 - week quit rates in pivotal trials. fier was discounted . The outcomes for abstinence associated with younger ages [ 0231 ] Effect Modification Analysis of Baseline Labora of initial smoking and with U.S. origins were poor . tory Markers Related to Smoking [ 0232 ] Baseline laboratory factors were analyzed for the TABLE 12 Cigarette Score primary outcome variable and Cess / W5-8 / Quit Rates in USA versus Non -USA CO Success comparing the cytisine 3.0 mg TID arm to the pooled placebo arm ( FIGS . 30 and 31 ) . These factors Varenicline Placebo included nicotine metabolism ratio (NMR ), expired CO , and CAR weeks 9-24 Versus placebo CAR weeks 9-24 serum cotinine , and were analyzed by median , tertiles, and Covariate % ( 95 % CI ) OR ( 95 % CI) % ( 95 % CI) quartiles . The same EMA models used for analyzing clinical sites were performed . The forest graphs for these analyses Region follow in FIG . 30 and FIG . 31. ( Note : In these forest graphs U.S. 16.1 ( 14.0-18.4 ) 2.66 ( 1.99-3.55 ) 6.7 ( 5.3-8.4) a ( M ) , ( T ), or ( Q ) at the end of a factor label indicates that Non - U.S . 27.9 ( 25.2-30.8 ) 2.80 ( 2.20-3.55 ) 12.2 ( 10.2-14.4 ) the pooled data were split by the median , tertiles, or quartiles , respectively .) [ 0233 ] Only the interaction P values of 0.0434 and 0.0652 [ 0224 ] FIG . 15 shows the odds ratio of cytisinicline at 4 for the median and tertile splits of baseline cotinine , respec weeks, end of treatment, and 4 weeks off treatment com tively , for the Cigarette Score met the criterion suggesting pared to current products. While the 94 % CI of the treat effect modification . However, the interaction P values for the ments marginally overlap, the odd ratios of the cytisinicline continued abstinence secondary outcome were 0.2925 , treatment are consistently better than that of NRT, Zyban® , 0.3738 , and 0.9732 for the median , tertile, and quartile and Chantix® . splits , respectively , showing no effect modification regard ing baseline cotinine levels . Since 4 -week abstinence is 1.6 Analysis of Baseline Attributes and Smoking Status planned to be the primary outcome for future Phase 3 [ 0225 ] Effect Modification Analysis of Baseline Patient studies, concern for baseline cotinine as an effect modifier is Attributes of less concern . [ 0226 ] A collection of baseline attributes including age , race , sex , duration of smoking, and number of quit attempts, 1.7 Tipping Point Analysis for Smoking Cessation Weeks were analyzed for both the Cigarette Score primary outcome 5-8 variable and Cess / W5-8 / CO Success ( FIGS . 26 and 27 ) . [ 0234 ] A tipping point analysis was performed for Cess / Only the comparison between the cytisine 3.0 mg TID arm W5-8 / CO Success for the cytisine 3.0 mg TID arm versus and the pooled placebo arm are presented . The same EMA the pooled placebo arm comparison and is shown in FIG . 32 . models used for analyzing clinical sites were used . The The goal of the tipping point analysis was to assess the forest graphs for these analyses follow . ( Note : In these forest degree to which the re - assignment of cases defined as failure graphs a ( M ) , ( T ) , or ( Q ) at the end of a factor label indicates due to inadequacy of assessment data would influence that the pooled data were split by the median , tertiles , or results . The tipping point evaluation re - analyzed the data for quartiles, respectively . Hx denotes " History ” . ) all possible reversals of the failure assignment to a success , [ 0227 ] The only interaction P value of note was that for the with a graph illustrating which re -assignments met statistical duration of smoking history split by quartiles ( “ Smoke Hx criterion . The horizontal axis represents the number of Dur ( y ) ( Q ” ) for the Cigarette Score , with P = 0.0800 . Since possible control arm re - assignments and the vertical axis the other smoking history duration variables did not have represents the number of possible experimental arm re significant P values ( P20.2566 ) this finding was regarded as assignments . Each combination of re - assignment was re unimportant. None of the other factors raised concern about analyzed to assess whether the statistical criterion was met . heterogeneity of effect. The lower left point represents the case where there are no US 2021/0077475 A1 Mar. 18 , 2021 22 re - assignments ( that is , the planned analysis ). The region or moderate on the TID schedule : One experienced a severe where re - assignments met statistical criterion is patterned , head injury, and another subject experienced a severe case of whereas the region where re -assignments do not meet sta influenza . Neither event was considered related to the study tistical criterion is grey . drug. TABLE 13 Summary of the TEAEs in the Study Population TID Downward Titration Pooled 1.5 mg 3.0 mg 1.5 mg 3.0 mg Cytisinicline Placebo ( n = 52 ) ( n = 50 ) ( n = 51 ) ( n = 50 ) ( n = 203 ) ( n = 51 ) At least 1 AE 20 ( 39 % ) 21 (42 % ) 29 ( 57 % ) 23 ( 46 % ) 93 ( 46 % ) 24 ( 47 % ) URTI 5 ( 10 % ) 3 (6 % ) 3 (6 %) 2 ( 4 % ) 13 ( 6 % ) 7 ( 14% ) Abnormal 4 ( 8 % ) 3 ( 6% ) 4 (8 % ) 7 ( 14 % ) 18 ( 9 %) 1 ( 2 % ) dreams Nausea 1 ( 2 %) 3 ( 6 % ) 5 ( 10% ) 3 (6 % ) 12 ( 6 % ) 5 ( 10 % ) Insomnia 4 ( 8 %) 3 ( 6 % ) 3 (6 % ) 4 ( 8% ) 14 ( 7 %) 1 ( 2 % ) Headache 6 ( 12 % ) 2 ( 4 % ) 1 (2 %) 1 ( 2 % ) 10 ( 5 % ) 2 ( 4 % ) Fatigue 3 ( 6 %) 1 (2 % ) 1 ( 2 % ) 2 ( 4 % ) 7 (3 % ) 2 ( 4 % ) Constipation 1 ( 2 % ) 3 ( 6 % ) 4 (2 % ) 1 ( 2% ) * 25 % ( 3 subjects ) in any treatment arm [ 0235 ] There were 6 control arm cases and 3 experimental [ 0239 ] There were no relevant mean changes or shifts arm cases that were eligible for re - assignment. The most from baseline in laboratory parameters over time or 12 - lead important finding from this graph is that if there either are 0 ECG results . The overall incidence of potentially clinically or 1 re - assignments in the experimental arm , then the significant changes in vital sign measurements was low , with statistical criterion will not be met when there are 3 or more the lowest incidence occurring on the TID schedule . re - assignments in the control arm . Similarly, if there either [ 0240 ] Table 14 summarizes the TEAEs of cytisinicline are 2 or 3 re - assignments in the experimental arm , then the compared to Chantix® in a previous 2016 study. TEAEs statistical criterion will not be met when there are 5 or more were experienced by less than 30 % the study population re - assignments in the control arm . Thus, the continued treated with either cytisinicline , Chantix® , or placebo . Sub abstinence secondary outcome was robust against re -assign jects treated with Chantix® experienced the highest inci ments . dence of TEAEs compared to cytisinicline and placebo. [ 0236 ] In summary , results for an initial quit rate at Week Most incidences of TEAEs with cytisinicline treatment was 4 for all cytisine - treated arms demonstrated significantly only marginally higher than placebo . increased initial rates ( 50 % to 54 % ) compared with pooled placebo ( 16 % ) , and with ORs ranging from 5.38 to 6.31 . TABLE 14 Prolonged abstinence from Weeks 5 to 8 ( i.e. , for 4 weeks off treatment) also demonstrated significantly increased pro TEAEs of cytisinicline compared to Chantix ® in 2016 Study longed quit rates of 16 % to 30 % in the cytisine - treated arms ORCA - 1 Cochrane compared to 8 % for pooled placebo and with ORs ranging from 3.23 to 5.04 . Overall, the initial and prolonged quit Cytisinicline Placebo Chantix ® rates were highest for the 3.0 mg TID arm at 54 % and 30 % , ( n = 203 ) ( n = 51 ) ( n > 7000 ) respectively, and with the greatest ORs of 6.31 and 5.04 , Serious AES 0 0 3.3 % respectively . Abnormal dreams 18 ( 9 % ) 1 (2 %) 12.5 % Headache 10 ( 5 % ) 2 ( 4 % ) 12.7 % Insomnia 14 ( 7 % ) 1 ( 2 % ) 14.2 % Safety Analysis Nausea 12 ( 6 % ) 5 ( 10 % ) 27.8 % [ 0237 ] Overall , there were no safety concerns following [ 0241 ] In summary, there were no serious or severe dosing in the 1.5 mg of cytisine or 3.0 mg treatment arms on adverse events and there was a low incidence of overall both schedules, and no new or unexpected AEs were iden adverse events . The results from the study further demon tified during the study . strate that there were no clinically - significant changes in [ 0238 ] Table 13 summarizes the treatment emergent vital signs, routine hematology and / or chemistry, and no adverse events ( TEAES ) . TEAEs were experienced by changes in ECG . Overall, no new safety signals were approximately half the study population in all treatment observed during the conduct of this study. arms. The TID dosing schedule had slightly fewer TEAEs overall. Across both schedules, the SOCs with the highest CONCLUSION incidence of TEAEs in any treatment arm were infections and infestations, psychiatric disorders, and gastrointestinal [ 0242 ] The results from the study indicated that cytisine disorders. Common TEAEs were AEs that had been previ benefit occurred all baseline characteristics and attributes . In ously reported in other studies or within the Investigator's specific, the cytisine benefit occurred across subject demo Brochure. All TEAEs were mild or moderate in severity on graphics, baseline CO levels and the number of cigarettes the commercial schedule and all events except 2 were mild smoked daily, as well as based on smoking history . In terms US 2021/0077475 A1 Mar. 18 , 2021 23 of subject demographics, the benefit was consistent across [ 0250 ] To assess whether subjects randomized to Arm B the subject population regardless of race , gender, age , and have a higher probability of abstinence from Week 3 to BMI . In addition , in terms of smoking history, regardless of Week 6 post - randomization as compared to subjects the duration of smoking , quit attempts, and history of prior randomized to Arm A ; and smoking cessation medication use ( e.g. , Chantix® , Zyban® , [ 0251 ] To assess whether subjects randomized to Arm C NRT, vaping ), the subjects exhibited the same benefit from have a higher probability of abstinence from Week 9 to administration of cytisine. Week 12 post - randomization as compared to subjects [ 0243 ] The results further demonstrated that subjects randomized to Arm A. exhibited a similar benefit upon administration of cytisine [ 0252 ] 2.1.2 Secondary Efficacy Objectives irrespective of their ability to metabolize nicotine . In par [ 0253 ] If the corresponding primary comparison passes ticular, no treatment relationship was observed based on the statistical criterion , then analysis for the following second baseline nicotine metabolite ratio of the subjects and there ary objectives will be performed . The secondary efficacy was a similar cytisine benefit for fast and slow nicotine objectives of the study will be the following: metabolizers . [ 0254 ] To assess whether subjects randomized to Arm B have a higher probability of continuous abstinence [ 0244 ] Results from the primary analyses demonstrated a from Week 6 to Week 24 post - randomization as com reduction in percentage of expected cigarettes smoked in pared to subjects randomized to Arm A ; and both schedules versus pooled placebo . Results for the initial [ 0255 ] To assess whether subjects randomized to Arm C quit rate endpoint demonstrated both cytisine arms of the have a higher probability of continuous abstinence TID schedule had high odds of success compared with from Week 12 to Week 24 post - randomization as com placebo ; subjects in the 3.0 mg of cytisine arm had the best pared to subjects randomized to Arm A. odds of success for quitting smoking at Week 4 . [ 0256 ] If the co - primary comparisons pass statistical cri [ 0245 ] For the prolonged abstinence from Week 5 to Week terion , then analysis for the following additional secondary 8 endpoint, both arms of the TID schedule had high odds of objective will be performed. The additional secondary effi success compared with placebo ; subjects in the 3.0 mg of cacy objective of the study will be the following: cytisine arm had the best odds of success for abstinence from [ 0257 ] To assess for a reduction in risk of relapse from Weeks 5 to 8. The study demonstrated that cytisine is an Week 6 to Week 24 in subjects receiving 3.0 mg effective aid to smoking cessation with an advantageous cytisinicline for 6 weeks and then either continue 3.0 adverse event profile , and 3.0 mg TID dosing is more mg cytisinicline from Week 6 to Week 12 ( Arm C ) or efficacious overall , with no increase in adverse events . were switched to placebo from Week 6 to Week 12 [ 0246 ] Overall, there were no safety concerns following ( Arm B ) . dosing in the 1.5 mg of cytisine or 3.0 mg arms on either [ 0258 ] Subjects not abstinent at Week 6 will be regarded schedule . as having relapsed . [ 0259 ] 2.1.3 Other Objectives Example 2 : Impact of Continued Treatment with [ 0260 ] Other objectives of this study will be the following: Cytisine on Smoking Cessation [ 0261 ] To compare arms ( Arm B versus Arm A ; Arm C [ 0247 ] This Example describes a Phase 3 , multi- center, versus Arm A ) on 7 - day point prevalence abstinence double - blind , randomized , placebo -controlled trial designed weekly at Week 2 to Week 12 , then for Weeks 16 , 20 , to evaluate the efficacy and safety of cytisine in adult and 24 ; smokers . This study is designed to improve efficacy out [ 0262 ] To compare arms ( Arm B versus Arm A ; Arm C comes and to determine whether continued treatment can versus Arm A ) on serum cotinine levels every other prevent early smoking relapse. The study is designed to week at Week 2 to Week 12 , then at Weeks 16 , 20 , and evaluate treatment across 3 treatment arms: placebo ( A ) , 24 ; treatment with cytisine ( e.g. , cytisinicline) for 6 weeks ( B ) , [ 0263 ] To compare arms ( Arm B versus Arm A ; Arm C and treatment with cytisine for 12 weeks ( C ) as shown in the versus Arm A ) on expired CO levels every week at schematic of FIG . 33. Subjects are randomized to one of the Week 2 through Week 12 , then at Weeks 16 , 20 , and 24 ; three arms A , B , or C. In Arm A , subjects are treated with a [ 0264 ] To compare arms ( Arm B versus Arm A ; Arm C placebo for 12 weeks plus behavioral support. In Arm B , versus Arm A ) on use of any non -cigarette nicotine subjects are treated with 3.0 mg cytisinicline TID for 6 products, including vaping, during study treatment at weeks followed by a placebo for 6 weeks plus behavioral Week 2 through Week 12 and study follow -up at Week support. In Arm C , subjects are treated with 3.0 mg cytisini 16 through Week 24 ; cline TID for 12 weeks plus behavioral support. Cytisine [ 0265 ] To assess whether subjects randomized to Arm B treatment will be evaluated in the study population for 6 or have a higher probability of abstinence from Week 9 to 12 weeks, with a primary efficacy endpoint of 4 -weeks of Week 12 as compared to subjects randomized to Arm A continuous abstinence while on treatment and will include a ( placebo ); 6 -month follow - up period . [ 0266 ] To assess among the subset of subjects who achieve abstinence from Week 3 to Week 6 , whether 2.1 Study Objectives subjects randomized to Arm B have a higher probabil ity of continuous abstinence from Week 3 to Week 24 [ 0248 ] 2.1.1 Co - Primary Efficacy Objectives post - randomization as compared to subjects random [ 0249 ] The co - primary efficacy objectives of the study , ized to Arm A ; which will be based on two comparisons where study [ 0267 ] To assess among the subset of subjects who success can be based on success for either comparison , will achieve abstinence from Week 9 to Week 12 , whether be the following: subjects randomized to Arm C have a higher probabil US 2021/0077475 A1 Mar. 18 , 2021 24

ity of continuous abstinence from Week 9 to Week 24 will take one study tablet three times during the day, post - randomization as compared to subjects random approximately 5 hours apart. Subjects randomly assigned to ized to Arm A ; Arm A will take one placebo tablet at each dosing per day [ 0268 ] Among subjects who achieve abstinence from for 12 weeks . Arm B subjects will take one cytisinicline Week 3 to Week 6 , to compare time to failure to tablet at each dosing per day for the first 6 weeks followed maintain abstinence between arms ( Arm B versus Arm by one placebo tablet at each dosing per day for the last 6 A ; Arm C versus Arm A ) to Week 24 ; weeks . Arm C subjects will take one cytisinicline tablet at [ 0269 ] To explore the magnitude of treatment effect each dosing per day for 12 weeks . between arms across various subgroups defined by [ 0281 ] 2.4 . Inclusion Criteria demographic and baseline characteristics for the pri [ 0282 ] Subjects meeting all of the following criteria will mary and secondary outcomes; and be eligible to participate in the study: [ 0270 ] To explore potential relationships between sub [ 0283 ] Male or female subjects years of age . ject- reported outcomes ( e.g. , anxiety, depression , with [ 0284 ] Current daily cigarette smokers ( averaging at drawal symptoms, and tobacco craving ) and the pri least 10 cigarettes per day upon completing a 7 - day mary and secondary outcomes . screening smoking diary ) and who intend to quit smok [ 0271 ] 2.1.4 Safety Objectives ing . [ 0272 ] The safety objectives of the study will be the [ 0285 ] Expired air CO O ppm . following: [ 0286 ] Failed at least one previous attempt to stop [ 0273 ] To evaluate the safety profile of 3.0 mg TID smoking with or without therapeutic support. cytisinicline compared to placebo ( e.g. , Arm B versus [ 0287 ] Willing to initiate study treatment on the day Arm A and Arm C versus Arm A ) ; after randomization and set a quit date within 5 to 7 [ 0274 ] To compare the safety profiles of Arm B subjects days of starting treatment. versus Arm C subjects with respect to adverse events [ 0288 ] Willing to actively participate in the study's occurring after Week 6 on the study . smoking cessation behavioral support provided throughout the study. 2.2 Study Design [ 0289 ] Able to fully understand study requirements , [ 0275 ] The population for this study will be male or willing to participate, and comply with dosing sched female adults who are daily cigarette smokers, intending to ule . quit smoking , and are willing to set a quit date that is within [ 0290 ] Sign the Informed Consent Form . 5 to 7 days of the start of treatment. Study treatment will start the day after randomization . 2.5 . Exclusion Criteria [ 0276 ] Subjects will meet all requirements outlined in [ 0291 ] Subjects will be excluded from participation in the inclusion and exclusion criteria . A total of approximately study if any of the following criteria apply : 750 subjects will be randomly assigned with equal prob [ 0292 ] More than 1 study participant in same house ability to one of three Arms ( Arm A , 12 weeks placebo: hold . N = 250 ; Arm B , 6 weeks cytisinicline followed by 6 weeks [ 0293 ] Previous cytisinicline treatment in a prior clini placebo : N = 250 ; Arm C , 12 weeks of cytisinicline : N = 250 ) cal study or any other cytisine usage . as shown in FIG . 33 . [ 0294 ] Known hypersensitivity to cytisinicline or any of [ 0277 ] Each randomized subject will receive 12 weeks of the excipients . treatment using a TID dosing schedule . Smoking cessation [ 0295 ] Positive urinary drugs of abuse screen deter assessments will begin on Week 2 ( Day 14 + 1 post -random mined within 28 days before the first dose of cytisini ization ) and will continue weekly during the Treatment cline . Period through the Week 16 , 20 , and 24 Follow - up Period [ 0296 ] Clinically significant abnormal serum chemistry visits by the subject's self- report of abstinence with CO or hematology values within 28 days of randomization biochemical verification . ( i.e. , requiring treatment or monitoring ). [ 0278 ] All subjects will receive concurrent smoking ces [ 0297 ] Clinically significant abnormalities in 12 - lead sation behavioral support during the study Treatment Period ECG determined after minimum of 5 minutes in supine (Week 1-12 ) . Additional behavioral support will be provided position within 28 days of randomization ( i.e. , requir during the follow - up Period based on issues , concerns , ing treatment or further assessment ). and / or questions raised by the subject. [ 0298 ] BMI classification for being underweight ( < 18.5 [ 0279 ) Safety assessments at clinic visits will occur on kg /m2 ) or having Class 2 obesity ( 35 kg /m2 ). Day 2 and Day 7 during Week 1 and then weekly throughout [ 0299 ] Recent history ( within 3 months ) of acute myo the Treatment Period . Laboratory hematology and chemistry cardial infarction , unstable angina, stroke, cerebrovas assessments will be made on Day 7 , Week 6 , and Week 12 cular incident, or hospitalization for congestive heart ( End of Treatment “ EOT" ) during the Treatment Period . failure . Any ongoing adverse events at Week 12 will be followed [ 0300 ] Current uncontrolled hypertension ( blood pres until resolved or determined to be chronic . The end of study sure 160/100 mmHg ). is defined as the last follow - up visit ( up to the Week 24 visit ) [ 0301 ] Documented diagnosis of schizophrenia or bipo for the last subject. lar psychiatric illness ; currently psychotic; having sui cidal ideation / risk ( “ Yes ” to question 4 or question 5 2.3 Treatment Period OR “ Yes” to any suicidal behavior question on the [ 0280 ] The Treatment Period will begin on the day after C - SSRS ) ; or current symptoms of moderate to severe randomization . Study treatment will be blinded , and subjects depression ( HADS score 1 ) . US 2021/0077475 A1 Mar. 18 , 2021 25

[ 0302 ] Renal impairment defined as a creatinine clear [ 0312 ] All concomitant medication ( s ) taken during the ance ( CrCl ) < 60 mL /min ( estimated with the Cockroft trial, and any changes ( additions, deletions, dose changes ) Gault equation ). will be recorded in the CRF . [ 0303 ] Hepatic impairment defined as alanine amino transferase ( ALT ) or aspartate aminotransferase ( AST ) 2.7 Treatment Compliance > 2.0x the upper limit of normal (ULN ). [ 0313 ] Treatment compliance will be monitored during the [ 0304 ] Women who are pregnant or breast - feeding. 84 - day ( 12 - week ) Treatment Period via review of dose [ 0305 ] Male or female subjects of child bearing poten timing and drug accountability . Subjects will have a daily tial who do not agree to use acceptable methods of birth treatment diary that will record the number of tablets taken control during the study treatment period . and time taken . Subjects will be instructed to bring their [ 0306 ] Participation in a clinical study with an investi medication packs ( blister packs ) to each clinic visit so that gational drug in the 4 weeks prior to randomization . clinic staff can reconcile against the treatment diary , record [ 0307 ] Treatment with other smoking cessation medi ing the number of tablets taken and the number of missed cations ( bupropion , varenicline , nortriptyline, or any tablets . In addition , an optional text messaging system will nicotine replacement therapy [NRT ]) in the 4 weeks be implemented that will provide each subject with reminder prior to randomization or planned use of these other texts corresponding to the approximate time of dosing . smoking cessation medications during the study. [ 0308 ] Use within the 2 weeks prior to randomization or 2.8 Study Procedures planned use during the study of non - cigarette and / or [ 0314 ] After providing signed informed consent, all sub noncombustible nicotine products (pipe tobacco , jects will be evaluated for inclusion in the study within a cigars, snuff, smokeless tobacco , hookah , e - cigarettes / 28 -day Screening Period . Subjects who meet inclusion cri vaping ) or marijuana smoking or vaping. teria will be required to provide a quit date that must be [ 0309 ] Any other reason that the investigator views the within 5-7 days after the start of treatment and agree to subject should not participate or would be unable to initiating study treatment the day after randomization . Both fulfill the requirements for the study. planned quit and treatment start dates will be documented to confirm inclusion . Once all eligibility criteria are confirmed , 2.6 Previous and Concomitant Medications randomization can occur. Study Day 1 will be defined as the first day of treatment . Subjects will complete a clinic visit on [ 0310 ) All subjects will continue to receive any existing Day 2 , 7 , 14 , 21 , 28 , 35 , 42 , 49 , 56 , 63 , 70 , 77 , and 86 . prescription medication . Every effort will be made to ensure Follow - up visits will be scheduled at Week 16 , 20 , and 24 . that the regimen of existing medications remain stable [ 0315 ] 2.8.1 Procedure Schedule during the study . [ 0316 ] Table 15 provides a summary of required study [ 0311 ] At the discretion of the Investigator, the use of evaluations . Screening evaluations will occur within a non - study drug medications ( either prescription or over - the 28 - day interval from initiation of screening evaluations to counter ) may be given if clinically -indicated during the randomization . Subjects will initiate study treatment the day study . Full details of any new medications will be recorded after randomization, such that study treatment is initiated on in the subject's Case Report Form ( CRF ) . Day 1 prior to the quit date , within 5-7 days of Day 1 . TABLE 15 Schedule of Study Procedures During Treatment Period Treatment Period Week 1 -Week 12 ( Day 84 ) Screening Period Random (Days 7-86 are 31 Day ) ( Day 28 to Rand) ization W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 EOT3 Study Assessment SV 1 SV 21 Day 0 D12 D2 ( D7 ) ( D14 ) ( D21 ) ( D28 ) ( D35 ) ( D42 ) ( D49 ) ( D56 ) ( D63 ) ( D70 ) ( D77 ) ( D86 ) Informed Consent Inclusion / Exclusion Demographics Medical and Psychiatric History C - SSRS Questionnaire Physical Exam Smoking History Urine Pregnancy Test for all Females Drugs of Abuse Screen ? Vital Signs including weight Hematology and Chemistry 12 - lead ECG Concomitant Medications US 2021/0077475 A1 Mar. 18 , 2021 26

TABLE 15 - continued Schedule of Study Procedures During Treatment Period Treatment Period Week 1 - Week 12 ( Day 84 ) Screening Period Random (Days 7-86 are 31 Day ) ( Day 28 to Rand ) ization W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 EOT3 Study Assessment SV 1 SV 21 Day 0 D12 D2 ( D7 ) ( D14 ) ( D21 ) ( D28 ) ( D35 ) ( D42 ) ( D49 ) ( D56 ) ( D63 ) ( D70 ) ( D77 ) ( D86 ) Quit Date Set and Treatment Day 1 Scheduled Review Smoking & Treatment Diary Completion Instructions Review Smoking Diary10 Review Treatment Diary Entries for Completeness and Compliancell Adverse Event Reporting Study Drug Distribution , Accountability, and Collection Behavioral Support , 12 Fagerström Test of Nicotine Dependence Self - Efficacy Questionnaire QSU - Brief Questionnaire MNWS Questionnaire 13 HADS Questionnaire Smoking Cessation Status Expired CO Use of any non cigarette nicotine products14 Serum Cotinine , 15 Randomization may occur at the SV2 visit IF subject can commit to a quit date that allows start of treatment the following day. In such cases , all Day 0 ( Randomization ) procedures will be completed at the SV2 clinic visit . 2Clinic will telephone each subject towards the end of Day 1 ( first day of treatment) to make sure subject has taken medication according to dosing schedule, answer any questions, assess for adverse events and any concomitant medications , and confirm the Day 2 clinic appointment. Procedures required at Day 86 or if subject discontinues treatment prior to Week 12. The final day of treatment will be on Day 84. In order to ensure subject completes all treatment prior to assessments , the End of Treatment visit will be scheduled on Day 86 = 1 Day . The Screening assessment for suicidal ideation ( questions 1-5 ) will be asked in the temporal context of “ within the past 3 months ” and the Suicidal Behavior questions will be asked within the temporal context of " within lifetime” in order to fully evaluate current ideation or risk of suicide. Assessments conducted at Week 6 and EOT will ask all questions in the temporal context of " since last assessment " for suicidal ideation / risk . SPhysical exam may be conducted at either the SV1 or the SV2 . Urine pregnancy test kits supplied to site by central laboratory . All other testing performed by a central laboratory . Test results must be negative at the SV1 and DO visit for inclusion into the study. ? Drugs of abuse to include at a minimum amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine , ecstasy, opiates , and phencyclidine . 8To include height at screening for BMI calculation . " There will be two distinct diaries to be used : The screening smoking diary will capture daily cigarette consumption for 7 consecutive days so that an average can be obtained to assess Inclusion Criteria # 2 . This on - study treatment diary will assess treatment compliance and will capture each study drug dose date and time . 10Number of cigarettes smoked daily will be recorded in a 7 - day smoking diary to be completed by the subject between SV1 and SV2 . Adequate completion of the 7 - day screening diary with an average of at least 10 cigarettes smoked per day will be required for inclusion into the study. Il Study subjects will make daily diary entries noting date and time of each dose . Sites will review these prior ( via on - line access ) and during clinic visits to ensure subject is completing entries in real - time and accurately. 12 Setting the quit date and plan will be considered the first behavioral support counseling session . 13The MNWS questionnaire to assess withdrawal will be administered to all subjects on Day 0 and Week 1 (Day 7 ) . Subsequent measurements will only be administered for subjects that report no cigarettes smoked since the last clinic visit . 144 Although planned use during the study is an exclusion criteria , record any actual use of non -cigarette nicotine products , including vaping . 15 Serum will be collected with other laboratory testing at SV # 1 for cotinine testing and another sample will be frozen / stored for possible Nicotine Metabolite Ratio ( NMR ) testing at baseline only. Serum collected on subjects that are screen - failed will be destroyed . US 2021/0077475 A1 Mar. 18 , 2021 27

TABLE 16 [ 0329 ] Safety will be assessed by consideration of all adverse events reported by or elicited from the subject and Schedule of Procedure During Follow - up Period abnormalities detected on hematology and serum chemistry Follow- up Period tests . Worsening of other pre - existing medical conditions Week 16 -Week 241 and any changes to concomitant medications / treatments will (Week Visits + 3 Days ) also be taken into account in this evaluation . [ 0330 ] 2.9.2 Laboratory Study Assessment Week 16 Week 20 Week 24 Behavioral Support Routine Laboratory Assessments Adverse Event Reporting Smoking Cessation Status [ 0331 ] Routine laboratory safety samples will be analyzed Expired CO at screening and at clinic visits as identified in Table 15 for Use of any non - cigarette nicotine products each subject by a central laboratory. A decision regarding Serum Cotinine whether a result outside the reference range is of clinical All subjects regardless of smoking status at Day 84 /Week 12 will continue for follow - up significance or not will be made by an Investigator, and the at the Week 16 , Week 20 , and Week 24 clinic visits . 2Behavioral support sessions during the Follow - up Period will be abbreviated and based report will be annotated accordingly. Clinically significant qnly on issues , concerns, and /or questions raised by subject for Week 16, 20 , and 24 . abnormalities occurring during the study will be recorded on Record any actual use of non - cigarette nicotine products , including vaping . the AE page . The reference ranges for laboratory parameters [ 0317 ] 2.8.2 Subject Diaries will also be entered in the database and filed in the Inves [ 0318 ) A7 - day smoking diary will be collected during the tigator site file. screening period in order to capture the number of cigarettes ( 0332 ] Hematology : Hemoglobin , red blood cells , white smoked daily for 7 consecutive days . This data will be used blood cells , neutrophils , lymphocytes, monocytes , eosino to calculate the average number of cigarettes smoked per phils, basophils , and platelets. day in order to support Inclusion Criteria # 2 . [ 0333 ] Chemistry : Total protein , albumin , total bilirubin , [ 0319 ] In addition , a study treatment diary will be main SGPT ( ALT ), SGOT ( AST ) , alkaline phosphatase , glucose , tained by each subject to record date and timing of study sodium , potassium , calcium , creatinine , and urea . drug administrations during the Treatment Period . The diary Expired Air CO will be configured into specific sections to support the above reporting by the subject. [ 0334 ] Expired CO will be obtained using a calibrated instrument ( e.g. , the Bedfont Micro + Smokerlyzer® ) pro 2.9 Efficacy Criteria vided and maintained by the clinical site . Each clinical site will have documentation of instrument used and current [ 0320 ] This study will follow general criteria that are calibration . CO values will be reported in parts per million applicable to previous and current trials of cessation aids ( ppm ) at Week 2 , weekly through Week 12 , and at Week 16 , where participants have a defined target quit date and there 20, and 24 . is face - to - face contact with researchers or clinic staff . End point analyses for abstinence ( 4 weeks abstinence docu Serum Cotinine Levels mented during the last 4 weeks of treatment) and continuous [ 0335 ] Serum samples will be collected for determining abstinence ( continually documented to Week 24 post -ran cotinine levels at Weeks 2 , 4 , 6 , 8 , 10 , 12 , 16 , 20 , and 24 . domization ) will include the following criteria : Baseline cotinine testing will use frozen serum collected at [ 0321 ] Self - report of smoking abstinence since the last the SV1 visit for subjects that are randomized . Cotinine clinic visit at each clinic assessment. levels will be determined at a central laboratory . [ 0322 ] Biochemical verification of abstinence by 10336 ] 2.9.3 Vital Signs expired CO at each clinic visit . [ 0337 ] Systolic / diastolic blood pressure , pulse rate , and [ 0323 ] Use of an ' intention - to - treat ' approach in which oral temperature measurements will be recorded in a seated data from all randomized smokers will be included in position . Body weight will also be recorded . Height will be the analysis . recorded at Screening Visit # 1 for BMI calculation . [ 0324 ] Subjects with an unknown smoking status at the [ 0338 ] 2.9.4 Physical Examination Week 6 , Week 12 , and Week 24 assessments or lost to [ 0339 ] A physical examination will be performed by an follow -up will be classified as failed to quit. Investigator. The examination will include general appear [ 0325 ] Self -report of smoking abstinence during the ance , head , ears , eyes, nose , throat, neck , skin , cardiovas follow -up period only (Week 12 to Week 24 ) will cular system , respiratory system , gastrointestinal system , follow the Russell Standard . central nervous system , lymph nodes, and musculoskeletal. [ 0326 ] Continually blinded to treatment allocation dur An Investigator can examine other body systems if required, ing collection of follow - up data to Week 24 . at their discretion . [ 0327 ] 2.9.1 Safety Assessments [ 0328 ] All subjects will be monitored for adverse events 2.10 Primary Outcome for Subjects starting at screening (pre - existing ), by telephone contact on [ 0340 ] The primary efficacy outcome ( biochemically veri Day 1 , at clinic visits on Day 2 and Day 7 during Week 1 , fied abstinence for the last 4 weeks of cytisinicline treat then weekly throughout the Treatment Period (Weeks 2 ment) for each subject will be binary : success versus failure . through 12 / EOT ) and monthly during the Follow - up Period Success will be defined for the subject as having reported ( see Table 15 and Table 16 ) . Laboratory ( hematology and smoking abstinence (no cigarettes since the last clinic visit ) chemistry ) evaluations will be performed at the Week 1 , at each clinic assessment from Week 3 to Week 6 ( Arm B ) Week 6 , and Week 12 clinic visits using a central laboratory. and Week 9 to Week 12 ( Arm C ) with biochemical verifi US 2021/0077475 A1 Mar. 18 , 2021 28 cation at each assessment. Biochemical verification will be [ 0351 ] The method of paragraphs 272-277 , wherein the defined by a carbon monoxide concentration in exhaled subject is a refractory patient who has failed treatment with breath of less than 10 ppm . Similar timeframe and analyses one or more nicotine addiction or smoking cessation treat will occur for Arm A placebo subjects . ments . [ 0352 ] The method of paragraphs 272-278 , wherein the 2.11 Secondary Outcome for Subjects nicotine addiction or smoking cessation treatments are selected from NRT, administration of bupropion , adminis [ 0341 ] The secondary efficacy outcome 1 and 2 ( continued tration of varenicline , electronic cigarettes, vaping , and a biochemically verified abstinence to Week 24 ) for each combination thereof. subject will be binary : success versus failure . Success will [ 0353 ] The method of paragraphs 272-279 , wherein the be defined for the subject as having reported smoking subject ( a ) smoked ten or more cigarettes per day prior to the abstinence since the last clinic visit at each clinic assessment administration of cytisine, ( b ) has expired air CO concen from Week 6 ( Arm B ) or Week 12 (Arm C ) to Week 24 with tration of about 10 ppm or greater prior to the administration biochemical verification at each assessment. Biochemical of cytisine, or ( c ) a combination of ( a ) and ( b ) . verification will be defined by a carbon monoxide concen [ 0354 ] The method of paragraphs 272-280 , further com tration in exhaled breath of less than 10 ppm . During the prising providing behavioral support to the subject. Follow - up Smoking Cessation Assessment Period between [ 0355 ] A method of treating of nicotine addiction and / or a Weeks 12 to 24 , self - report of smoking abstinence will be nicotine dependence in a subject in need thereof, the method according to the Russell Standard . comprising administering cytisine to the subject, wherein [ 0342 ] The secondary efficacy outcome 3 will be success the subject is a refractory patient who has failed treatment with respect to being without relapse at Week 24. The with one or more nicotine addiction treatments . secondary efficacy outcome 3 ( reduction in risk of relapse [ 0356 ] The method of paragraph 282 , wherein the nicotine from Week 6 to Week 24 in Arm C versus Arm B ) will be addiction treatments comprise NRT, administration of assessed in each subject ( in both Arms C and B ) . Subjects bupropion , administration of varenicline, electronic ciga not abstinent at Week 6 will be regarded as having relapsed . rettes, vaping, or a combination thereof. [ 0357 ] The method of paragraphs 282 and 283 , wherein 2.12 Safety Objectives cytisine is provided in a unit dose of about 1.0 mg to about 6.0 mg of cytisine three to six times daily to a subject in need [ 0343 ] Safety assessments will include reported adverse thereof . events , laboratory test results , and vital signs . Safety vari [ 0358 ] The method of paragraphs 282-284 , wherein ables will be summarized for the Safety Analysis Set ( SAS ) , cytisine is provided in a unit dose of 3.0 mg of cytisine three defined as all randomized subjects who take at least one dose times daily to a subject in need thereof. of study drug. [ 0359 ] The method of paragraphs 282-285 , wherein the [ 0344 ] Adverse events will be coded using the MedDRA unit dose of cytisine comprises ( a ) two tablets , each tablet dictionary. Coding will include system organ class ( SOC ) either containing 1.5 mg or 3.0 mg of cytisine , ( b ) a single and preferred term ( PT ) . All verbatim descriptions and tablet either containing 1.5 mg or 3.0 mg of cytisine, or ( c ) coded terms will be listed for all AEs . Various embodiments three tablets, each tablet containing 1.0 mg of cytisine . of the invention are set forth herein below in paragraphs 272 [ 0360 ] The method of paragraphs 282-286 , wherein to 391 : cytisine is administered for about 6 weeks or for about 12 [ 0345 ] A method of treating a nicotine addiction, a nico weeks . tine dependence , promoting cessation of smoking and /or [ 0361 ] The method of paragraphs 282-287 , wherein the vaping , and / or promoting a reduction in smoking and / or subject experiences no adverse events after receiving the vaping in a subject in need thereof, the method comprising cytisine treatment. administering cytisine provided in a unit dose of 3.0 mg , 1.5 [ 0362 ] The method of paragraphs 282-288 , wherein the mg , or 1.0 mg of cytisine three times daily to the subject. adverse event is selected from the group consisting of an [ 034 ] The method of paragraph 272 , wherein the subject URTI, abnormal dreams, nausea , insomnia, headache, experiences no adverse events after receiving the cytisine fatigue, and constipation . treatment. [ 0363 ] The method of paragraphs 282-289 , wherein the [ 0347 ] The method of paragraphs 272 and 273 , wherein subject ( a ) smoked ten or more cigarettes per day prior to the the adverse event is selected from the group consisting of an administration of cytisine, ( b ) has expired air CO concen URTI, abnormal dreams, nausea, insomnia , headache, tration of about 10 ppm or greater prior to the administration fatigue , and constipation . of cytisine, or ( c ) a combination of ( a ) and ( b ) . [ 0364 ] A method of preventing smoking and / or vaping [ 0348 ] The method of paragraphs 272-274 , wherein the relapse in a subject in need thereof, the method comprising subject experiences no nausea after receiving the cytisine administering cytisine provided in a unit dose of ( a ) two treatment. tablets , each tablet either containing 1.5 mg or 3.0 mg of [ 0349 ] The method of paragraphs 272-275 , wherein cytisine, ( b ) a single tablet either containing 1.5 mg or 3.0 cytisine is administered for about 6 weeks or for about 12 mg of cytisine , or ( c ) three tablets, each tablet containing 1.0 weeks . mg of cytisine , three times daily to the subject. [ 0350 ] The method of paragraphs 272-276 , wherein the [ 0365 ] The method of paragraph 291 , wherein cytisine is unit dose of cytisine comprises ( a ) two tablets , each tablet administered for about 6 weeks or for about 12 weeks . either containing 1.5 mg or 3.0 mg of cytisine, ( b ) a single [ 0366 ] The method of paragraphs 291 and 292 , wherein tablet either containing 1.5 mg or 3.0 mg of cytisine , or ( c ) the subject experiences no adverse events after receiving the three tablets, each tablet containing 1.0 mg of cytisine. cytisine treatment. US 2021/0077475 A1 Mar. 18 , 2021 29

[ 0367 ] The method of paragraphs 291-293 , wherein the single tablet either containing 1.5 mg or 3.0 mg of cytisine , adverse event is selected from the group consisting of an or ( c ) three tablets , each tablet containing 1.0 mg of cytisine . URTI, abnormal dreams, nausea , insomnia , headache, [ 0381 ] The medicament of paragraphs 302-307 , wherein fatigue, and constipation . the subject is a refractory patient who has failed treatment [ 0368 ] The method of paragraphs 291-294 , wherein the with one or more nicotine addiction or smoking cessation subject ( a ) smoked ten or more cigarettes per day prior to the treatments . administration of cytisine , ( b ) has expired air CO concen [ 0382 ] The medicament of paragraphs 302-308 , wherein tration of about 10 ppm or greater prior to the administration the nicotine addiction or smoking cessation treatments are of cytisine , or ( c ) a combination of ( a ) and ( b ) . selected from NRT, administration of bupropion , adminis [ 0369 ] The method of paragraphs 291-295 , wherein the tration of varenicline, electronic cigarettes , vaping , and a subject is a refractory patient who has failed treatment with combination thereof. one or more smoking cessation treatments . [ 0383 ] The medicament of paragraphs 302-309 , wherein [ 0370 ] The method of paragraphs 291-296 , wherein the the subject ( a ) smoked ten or more cigarettes per day prior smoking cessation treatments comprise NRT, administration to the administration of cytisine, ( b ) has expired air CO of bupropion , administration of varenicline , electronic ciga concentration of about 10 ppm or greater prior to the rettes, vaping, or a combination thereof. administration of cytisine, or ( c ) a combination of ( a ) and [ 0371 ] A method of preventing smoking and / or vaping ( b ) . relapse in a subject in need thereof, the method comprising [ 0384 ] The medicament of paragraphs 302-310 , further administering cytisine to the subject, wherein the subject is comprising providing behavioral support to the subject. a refractory patient who has failed treatment with one or [ 0385 ] A medicament comprising cytisine for treating a more smoking cessation treatments selected from the group nicotine addiction or a nicotine dependence in a subject that consisting of NRT, administration of bupropion , administra is a refractory patient who has failed treatment with one or tion of varenicline , electronic cigarettes, and vaping . more nicotine addiction treatments , wherein the medicament [ 0372 ] The method of paragraph 298 , wherein the subject is for three times daily oral administration to the subject. ( a ) smoked ten or more cigarettes per day prior to the [ 0386 ] The medicament of paragraph 312 , wherein the administration of cytisine , ( b ) has expired air CO concen nicotine addiction or dependence treatments comprise NRT, tration of about 10 ppm or greater prior to the administration administration of bupropion , administration of varenicline , of cytisine , or ( c ) a combination of ( a ) and ( b ) . electronic cigarettes, vaping, or a combination thereof. [ 0373 ] The method of paragraphs 298 and 299 , wherein [ 0387 ] The medicament of paragraphs 312 and 313 , the unit dose of cytisine comprises ( a ) two tablets, each wherein cytisine is provided in a unit dose of about 1.0 mg tablet either containing 1.5 mg or 3.0 mg of cytisine, ( b ) a to about 6.0 mg of cytisine three to six times daily to a single tablet either containing 1.5 mg or 3.0 mg of cytisine , subject in need thereof. or ( c ) three tablets, each tablet containing 1.0 mg of cytisine , [ 0388 ] The medicament of paragraphs 312-314 , wherein and wherein cytisine is administered for about 6 weeks or for cytisine is provided in a unit dose of 3.0 mg of cytisine three about 12 weeks . times daily to a subject in need thereof. [ 0374 ] The method of paragraphs 298-300 , wherein the [ 0389 ] The medicament of paragraphs 312-315 , wherein subject experiences no adverse events selected from the the unit dose of cytisine comprises ( a ) two tablets, each group consisting of an URTI, abnormal dreams, nausea , tablet either containing 1.5 mg or 3.0 mg of cytisine, ( b ) a insomnia, headache , fatigue, and constipation after receiving single tablet either containing 1.5 mg or 3.0 mg of cytisine , the cytisine treatment. or ( c ) three tablets , each tablet containing 1.0 mg of cytisine. [ 0375 ] A medicament comprising a unit dose of 3.0 mg , [ 0390 ] The medicament of paragraphs 312-316 , wherein 1.5 mg , or 1.0 mg of cytisine for treating a nicotine addic cytisine is administered for about 6 weeks or for about 12 tion , a nicotine dependence, promoting cessation of smoking weeks. and / or vaping , and / or promoting a reduction in smoking [ 0391 ] The medicament of paragraphs 312-317 , wherein and / or vaping in a subject in need thereof, wherein the the subject experiences no adverse events after receiving the medicament is for three times daily oral administration to cytisine treatment. the subject. [ 0392 ] The medicament of paragraphs 312-318 , wherein the adverse event is selected from the group consisting of an [ 0376 ] The medicament of paragraph 302 , wherein the URTI, abnormal dreams, nausea , insomnia, headache , subject experiences no adverse events after receiving the fatigue , and constipation. cytisine treatment. [ 0393 ] The medicament of paragraphs 312-319 , wherein [ 0377 ] The medicament of paragraphs 302 and 303 , the subject ( a ) smoked ten or more cigarettes per day prior wherein the adverse event is selected from the group con to the administration of cytisine, ( b ) has expired air CO sisting of an URTI, abnormal dreams, nausea , insomnia , concentration of about 10 ppm or greater prior to the headache , fatigue, and constipation. administration of cytisine, or ( c ) a combination of ( a ) and [ 0378 ] The medicament of paragraphs 302-304 , wherein ( b ). the subject experiences no nausea after receiving the cytisine [ 0394 ] A medicament comprising a unit dose of cytisine in treatment. ( a ) two tablets , each tablet either containing 1.5 mg or 3.0 [ 0379 ] The medicament of paragraphs 302-305 , wherein mg of cytisine , ( b ) a single tablet either containing 1.5 mg cytisine is administered for about 6 weeks or for about 12 or 3.0 mg of cytisine, or ( c ) three tablets , each tablet weeks. containing 1.0 mg of cytisine for preventing smoking and / or [ 0380 ] The medicament of paragraphs 302-306 , wherein vaping relapse in a subject in need thereof, wherein the the unit dose of cytisine comprises ( a ) two tablets, each medicament is for three times daily oral administration to tablet either containing 1.5 mg or 3.0 mg of cytisine , ( b ) a the subject. US 2021/0077475 A1 Mar. 18 , 2021 30

[ 0395 ] The medicament of paragraph 321 , wherein [ 0409 ] The use of paragraphs 332-335 , wherein cytisine is cytisine is administered for about 6 weeks or for about 12 administered for about 6 weeks or for about 12 weeks . weeks . [ 0410 ] The use of paragraphs 332-336 , wherein the unit [ 0396 ] The medicament of paragraphs 321 and 322 , dose of cytisine comprises ( a ) two tablets , each tablet either wherein the subject experiences no adverse events after containing 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet receiving the cytisine treatment. either containing 1.5 mg or 3.0 mg of cytisine , or ( c ) three [ 0397 ] The medicament of paragraphs 321-323 , wherein tablets , each tablet containing 1.0 mg of cytisine. the adverse event is selected from the group consisting of an [ 0411 ] The use of paragraphs 332-337 , wherein the subject URTI, abnormal dreams, nausea , insomnia , headache , is a refractory patient who has failed treatment with one or fatigue , and constipation . more nicotine addiction or smoking cessation treatments . [ 0398 ] The medicament of paragraphs 321-324 , wherein [ 0412 ] The use paragraphs 332-338 , wherein the nicotine the subject ( a ) smoked ten or more cigarettes per day prior addiction or smoking cessation treatments are selected from to the administration of cytisine , ( b ) has expired air CO NRT, administration of bupropion , administration of vareni concentration of about 10 ppm or greater prior to the cline , electronic cigarettes, vaping , and a combination administration of cytisine, or ( c ) a combination of ( a ) and thereof. ( b ) . [ 0413 ] The use of paragraphs 332-339 , wherein the sub [ 0399 ] The medicament of paragraphs 321-325 , wherein ject ( a ) smoked ten or more cigarettes per day prior to the the subject is a refractory patient who has failed treatment administration of cytisine, ( b ) has expired air CO concen with one or more smoking cessation treatments . tration of about 10 ppm or greater prior to the administration [ 0400 ] The medicament of paragraphs 321-326 , wherein of cytisine, or ( c ) a combination of ( a ) and ( b ) . the smoking cessation treatments comprise NRT, adminis [ 0414 ] The use of paragraphs 332-340 , further comprising tration of bupropion , administration of varenicline, elec providing behavioral support to the subject. tronic cigarettes, vaping, or a combination thereof. [ 0415 ] Use of cytisine for treating a nicotine addiction or [ 0401 ] A medicament comprising cytisine for preventing a nicotine dependence in a subject that is a refractory patient smoking and / or vaping relapse in a subject that is a refrac who has failed treatment with one or more nicotine addiction tory patient who has failed treatment with one or more treatments , wherein the cytisine is for three times daily oral nicotine addiction treatments selected from the group con administration to the subject. sisting of NRT, administration of bupropion , administration [ 0416 ] The use of paragraph 342 , wherein the nicotine of varenicline, electronic cigarettes, and vaping, wherein the addiction treatments comprise NRT, administration of medicament is for three times daily oral administration to bupropion , administration of varenicline, electronic ciga the subject. rettes , vaping , or a combination thereof . [ 0402 ] The medicament of paragraph 328 , wherein the [ 0417 ] The use of paragraphs 342 and 343 , wherein subject ( a ) smoked ten or more cigarettes per day prior to the cytisine is provided in a unit dose of about 1.0 mg to about administration of cytisine , ( b ) has expired air CO concen 6.0 mg of cytisine three to six times daily to a subject in need tration of about 10 ppm or greater prior to the administration thereof. of cytisine , or ( c ) a combination of ( a ) and ( b ) . [ 0418 ] The use of paragraphs 342-344 , wherein cytisine is [ 0403 ] The medicament of paragraphs 328 and 329 , provided in a unit dose of 3.0 mg of cytisine three times wherein the unit dose of cytisine comprises ( a ) two tablets, daily to a subject in need thereof. each tablet either containing 1.5 mg or 3.0 mg of cytisine, ( b ) [ 0419 ] The use of paragraphs 342-345 , wherein the unit a single tablet either containing 1.5 mg or 3.0 mg of cytisine , dose of cytisine comprises ( a ) two tablets, each tablet either or ( c ) three tablets, each tablet containing 1.0 mg of cytisine , containing 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet and wherein cytisine is administered for about 6 weeks or for either containing 1.5 mg or 3.0 mg of cytisine , or ( c ) three about 12 weeks . tablets , each tablet containing 1.0 mg of cytisine. [ 0404 ] The medicament of paragraphs 328-330 , wherein [ 0420 ] The use of paragraphs 342-346 , wherein cytisine is the subject experiences no adverse events selected from the administered for about 6 weeks or for about 12 weeks . group consisting of an URTI, abnormal dreams, nausea , [ 0421 ] The use of paragraphs 342-347 , wherein the sub insomnia, headache , fatigue , and constipation after receiving ject experiences no adverse events after receiving the the cytisine treatment. cytisine treatment. [ 0405 ] Use of a unit dose of 3.0 mg , 1.5 mg , or 1.0 mg of [ 0422 ] The use of paragraphs 342-348 , wherein the cytisine for treating a nicotine addiction , a nicotine depen adverse event is selected from the group consisting of an dence , promoting cessation of smoking and / or vaping, and / URTI, abnormal dreams, nausea , insomnia, headache , or promoting a reduction in smoking and / or vaping in a fatigue, and constipation . subject in need thereof, wherein the cytisine is for three [ 0423 ] The use of paragraphs 342-349 , wherein the sub times daily oral administration to the subject. ject ( a ) smoked ten or more cigarettes per day prior to the [ 0406 ] The use of paragraph 332 , wherein the subject administration of cytisine, ( b ) has expired air CO concen experiences no adverse events after receiving the cytisine tration of about 10 ppm or greater prior to the administration treatment. of cytisine , or ( c ) a combination of ( a ) and ( b ) . [ 0407 ] The use of paragraphs 332 and 333 , wherein the [ 0424 ] Use of a unit dose of cytisine in the form of ( a ) two adverse event is selected from the group consisting of an tablets , each tablet either containing 1.5 mg or 3.0 mg of URTI, abnormal dreams, nausea, insomnia , headache, cytisine , ( b ) a single tablet either containing 1.5 mg or 3.0 fatigue, and constipation . mg of cytisine , or ( c ) three tablets, each tablet containing 1.0 [ 0408 ] The use of paragraphs 332-334 , wherein the sub mg of cytisine for preventing smoking and /or vaping relapse ject experiences no nausea after receiving the cytisine treat in a subject in need thereof, wherein the cytisine is for three ment. times daily oral administration to the subject. US 2021/0077475 A1 Mar. 18 , 2021 31

[ 0425 ] The use of paragraph 351 , wherein cytisine is [ 0440 ] The use of paragraphs 362-366 , wherein a unit administered for about 6 weeks or for about 12 weeks . dose of cytisine comprises ( a ) two tablets , each tablet either [ 0426 ] The use of paragraphs 351 and 352 , wherein the containing 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet subject experiences no adverse events after receiving the either containing 1.5 mg or 3.0 mg of cytisine , or ( c ) three cytisine treatment tablets , each tablet containing 1.0 mg of cytisine. [ 0427 ] The use of paragraphs 351-353 , wherein the [ 0441 ] The use of paragraphs 362-367 , wherein the sub adverse event is selected from the group consisting of an ject is a refractory patient who has failed treatment with one URTI, abnormal dreams, nausea , insomnia , headache, or more nicotine addiction or smoking cessation treatments . fatigue, and constipation . [ 0442 ] The use of paragraphs 362-368 , wherein the nico [ 0428 ] The use of paragraphs 351-354 , wherein the sub tine addiction or smoking cessation treatments are selected ject ( a ) smoked ten or more cigarettes per day prior to the from NRT, administration of bupropion , administration of administration of cytisine , ( b ) has expired air CO concen varenicline, electronic cigarettes, vaping , and a combination tration of about 10 ppm or greater prior to the administration thereof. [ 0443 ] The use of paragraphs 362-369 , wherein the sub of cytisine , or ( c ) a combination of ( a ) and ( b ) . ject ( a ) smoked ten or more cigarettes per day prior to the [ 0429 ] The use of paragraphs 351-355 , wherein the sub administration of cytisine , ( b ) has expired air CO concen ject is a refractory patient who has failed treatment with one tration of about 10 ppm or greater prior to the administration or more smoking cessation treatments . of cytisine, or ( c ) a combination of ( a ) and ( b ) . [ 0430 ] The use of paragraphs 351-356 , wherein the smok [ 0444 ] The use of paragraphs 362-370 , further comprising ing cessation treatments comprise NRT, administration of providing behavioral support to the subject. bupropin , administration of varenicline, electronic ciga [ 0445 ] Use of tablets comprising about 1.0 mg or about rettes , vaping, or a combination thereof. 1.5 mg of cytisine for three times daily oral administration [ 0431 ] Use of cytisine for preventing smoking and / or of about 3.0 mg of cytisine to a subject that is a refractory vaping relapse in a subject that is a refractory patient who patient who has failed treatment with one or more nicotine has failed treatment with one or more nicotine addiction addiction treatments to treat a nicotine addiction and / or a treatments selected from the group consisting of NRT, nicotine dependence in the subject. administration of bupropion , administration of varenicline, [ 0446 ] The use of paragraph 372 , wherein the nicotine electronic cigarettes, and vaping, wherein the cytisine is for addiction treatments comprise NRT, administration of three times daily oral administration to the subject. bupropion , administration of varenicline, electronic ciga [ 0432 ] The use of paragraph 358 , wherein the subject ( a ) rettes , vaping, or a combination thereof. smoked ten or more cigarettes per day prior to the admin [ 0447 ] The use of paragraphs 372 and 373 , wherein istration of cytisine, ( b ) has expired air CO concentration of cytisine is provided in a unit dose of about 1.0 mg to about about 10 ppm or greater prior to the administration of 6.0 mg of cytisine three to six times daily to a subject in need cytisine, or ( c ) a combination of ( a ) and ( b ). thereof . [ 0433 ] The use of paragraphs 358 and 359 wherein the [ 0448 ] The use of paragraphs 372-374 , wherein cytisine is unit dose of cytisine comprises ( a ) two tablets , each tablet provided in a unit dose of 3.0 mg of cytisine three times either containing 1.5 mg or 3.0 mg of cytisine, ( b ) a single daily to a subject in need thereof. tablet either containing 1.5 mg or 3.0 mg of cytisine, or ( c ) [ 0449 ] The use of paragraphs 372-375 , wherein the unit three tablets , each tablet containing 1.0 mg of cytisine , and dose of cytisine comprises either ( a ) two tablets, each tablet wherein cytisine is administered for about 6 weeks or for containing 1.5 mg of cytisine, or ( b ) a single tablet contain about 12 weeks . ing 3.0 mg of cytisine . [ 0434 ] The use of paragraphs 358-360 , wherein the sub [ 0450 ] The use of paragraphs 372-376 , wherein cytisine is ject experiences no adverse events selected from the group administered for about 6 weeks or for about 12 weeks . consisting of an URTI, abnormal dreams, nausea , insomnia , [ 0451 ] The use of paragraphs 372-377 , wherein the sub headache , fatigue , and constipation after receiving the ject experiences no adverse events after receiving the cytisine treatment. cytisine treatment. [ 0435 ] Use of tablets comprising about 1.0 mg or about [ 0452 ] The use of paragraphs 372-378 , wherein the 1.5 mg of cytisine for three times daily oral administration adverse event is selected from the group consisting of an of about 3.0 mg of cytisine to a subject to treat a nicotine URTI, abnormal dreams, nausea , insomnia, headache, addiction , a nicotine dependence, promoting cessation of fatigue , and constipation . smoking and / or vaping, and / or promoting a reduction in [ 0453 ] The use of paragraphs 372-379 , wherein the sub smoking and / or vaping in the subject. ject ( a ) smoked ten or more cigarettes per day prior to the [ 0436 ] The use of paragraph 362 , wherein the subject administration of cytisine, ( b ) has expired air CO concen experiences no adverse events after receiving the cytisine tration of about 10 ppm or greater prior to the administration treatment. of cytisine, or ( c ) a combination of ( a ) and ( b ) . [ 0437 ] The use of paragraphs 362 and 363 , wherein the [ 0454 ] Use of tablets comprising about 1.0 mg or about adverse event is selected from the group consisting of an 1.5 mg of cytisine for three times daily oral administration URTI, abnormal dreams, nausea , insomnia , headache, of about 3.0 mg of cytisine to a subject to prevent smoking fatigue, and constipation . and /or vaping relapse in the subject. [ 0438 ] The use of paragraphs 362-364 , wherein the sub [ 0455 ] The use of paragraph 381 , wherein cytisine is ject experiences no nausea after receiving the cytisine treat administered for about 6 weeks or for about 12 weeks . ment. [ 0456 ] The use of paragraphs 381 and 382 , wherein the [ 0439 ] The use of paragraphs 362-365 , wherein cytisine is subject experiences no adverse events after receiving the administered for about 6 weeks or for about 12 weeks . cytisine treatment. US 2021/0077475 A1 Mar. 18 , 2021 32

[ 0457 ] The use of paragraphs 381-383 , wherein the administering cytisine provided in a unit dose of ( a ) two adverse event is selected from the group consisting of an tablets , each tablet either containing 1.5 mg or 3.0 mg of upper respiratory tract infection (URTI ), abnormal dreams, cytisine, ( b ) a single tablet either containing 1.5 mg or 3.0 nausea , insomnia, headache , fatigue , and constipation . mg of cytisine, or ( c ) three tablets, each tablet containing 1.0 [ 0458 ] The use of paragraphs 381-384 , wherein the sub mg of cytisine , three times daily to the subject. ject ( a ) smoked ten or more cigarettes per day prior to the 21. The method of claim 20 , wherein cytisine is admin administration of cytisine , ( b ) has expired air CO concen istered for about 6 weeks or for about 12 weeks . tration of about 10 ppm or greater prior to the administration 22. The method of claim 20 , wherein the subject experi of cytisine , or ( c ) a combination of ( a ) and ( b ) . ences no adverse events after receiving the cytisine treat [ 0459 ] The use of paragraphs 381-385 , wherein the sub ject is a refractory patient who has failed treatment with one ment . or more smoking cessation treatments . 23. The method of claim 22 , wherein the adverse event is [ 0460 ] The use of paragraphs 381-386 , wherein the smok selected from the group consisting of an URTI, abnormal ing cessation treatments comprise NRT, administration of dreams, nausea , insomnia, headache , fatigue , and constipa bupropion , administration of varenicline , electronic ciga tion . rettes , vaping, or a combination thereof. 24. The method of claim 20 , wherein the subject ( a ) [ 0461 ] Use of tablets comprising about 1.0 mg or about smoked ten or more cigarettes per day prior to the admin 1.5 mg of cytisine for three times daily oral administration istration of cytisine , ( b ) has expired air CO concentration of of about 3.0 mg of cytisine to a subject who has failed about 10 ppm or greater prior to the administration of treatment with one or more nicotine addiction treatments cytisine, or ( c ) a combination of ( a ) and ( b ) . selected from the group consisting of NRT, administration of The method of claim 20 , wherein the subject is a bupropion , administration of varenicline, electronic ciga refractory patient who has failed treatment with one or more rettes , and vaping to prevent smoking relapse in the subject. smoking cessation treatments . [ 0462 ] The use of paragraph 388 , wherein the subject ( a ) 26. The method of claim 25 , wherein the smoking ces smoked ten or more cigarettes per day prior to the admin sation treatments comprise NRT, administration of bupro istration of cytisine, ( b ) has expired air CO concentration of pion , administration of varenicline , electronic cigarettes, about 10 ppm or greater prior to the administration of vaping , or a combination thereof. cytisine, or ( c ) a combination of ( a ) and ( b ). 27. A method of preventing smoking and / or vaping [ 0463 ] The use of paragraphs 388 and 389 , wherein a unit relapse in a subject in need thereof, the method comprising dose of cytisine comprises ( a ) two tablets , each tablet either administering cytisine to the subject, wherein the subject is containing 1.5 mg or 3.0 mg of cytisine, ( b ) a single tablet a refractory patient who has failed treatment with one or either containing 1.5 mg or 3.0 mg of cytisine, or ( c ) three more smoking cessation treatments selected from the group tablets, each tablet containing 1.0 mg of cytisine, and consisting of NRT, administration of bupropion , administra wherein cytisine is administered for about 6 weeks or for tion of varenicline, electronic cigarettes, vaping . about 12 weeks . 28. The method of claim 27 , wherein the subject ( a ) [ 0464 ] The use of paragraphs 388-390 , wherein the sub smoked ten or more cigarettes per day prior to the admin ject experiences no adverse events selected from the group istration of cytisine, ( b ) has expired air CO concentration of consisting of an URTI, abnormal dreams , nausea , insomnia, headache, fatigue, and constipation after receiving the about 10 ppm or greater prior to the administration of cytisine treatment. cytisine, or ( c ) a combination of ( a ) and ( b ) . 1-10 . ( canceled) 29. The method of claim 27 , wherein the unit dose of 11. A method of treating of nicotine addiction in a subject cytisine comprises ( a ) two tablets , each tablet either con in need thereof, the method comprising administering taining 1.5 mg or 3.0 mg of cytisine , ( b ) a single tablet either cytisine to the subject, wherein the subject is a refractory containing 1.5 mg or 3.0 mg of cytisine, or ( c ) three tablets , patient who has failed treatment with one or more nicotine each tablet containing 1.0 mg of cytisine , and wherein addiction treatments . cytisine is administered for about 6 weeks or for about 12 12. The method of claim 11 , wherein the nicotine addic weeks . tion treatments comprise NRT, administration of bupropion , 30. The method of claim 27 , wherein the subject experi administration of varenicline , electronic cigarettes, vaping, ences no adverse events selected from the group consisting or a combination thereof. of an URTI, abnormal dreams, nausea , insomnia , headache, 13-19 . ( canceled) fatigue , and constipation after receiving the cytisine treat 20. A method of preventing smoking and / or vaping ment. relapse in a subject in need thereof, the method comprising