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Cytisinicline

Phase 3

Smoking Cessation | Small molecule | Other |Achieve Life Sciences, Inc.|Last Updated: Jan 15, 2026

Success Probability
Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
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Market & Valuation
rNPV $3.2B
Market Size $9.4B
Revenue Basis $1.6B
Competitors 6
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Trial Design
RandomizedDouble-BlindCONTROLLEDDMCBiomarker
Total Trials5
Total Enrollment2,138
FDA Designations
BREAKTHROUGH_THERAPY
Clinical Trials (5)
NCT IDTitlePhaseStatusEnrollmentVelocityDesignStartCompletionLast UpdatedSitesCountries
NCT06435221Safety Study of Cytisinicline in Adult Combustible and/or E-cigarette SmokersPHASE3 COMPLETED 479 — — May 28, 2024Oct 6, 2025Nov 26, 202529 United States
NCT05206370A Second Study of Cytisinicline for Smoking Cessation in Adult SmokersPHASE3 COMPLETED 792 — — Jan 20, 2022Mar 21, 2023Jan 14, 202612 United States
NCT04576949A Study of Cytisinicline for Smoking Cessation in Adult SmokersPHASE3 COMPLETED 810 — — Oct 13, 2020Dec 23, 2021Jan 15, 202617 United States
NCT05981768Study to Evaluate Effect of Food on Bioavailability of Single 3 mg Tablet and Pharmacokinetics (PK) of Multiple 3 mg Doses in Healthy Adult SmokersPHASE1 COMPLETED 30 — — Aug 8, 2023Sep 21, 2023Oct 18, 20231 Portugal
NCT05566288Study to Evaluate Electrocardiographic Effects of Therapeutic & Supratherapeutic Doses of Cytisinicline in Healthy SmokersPHASE1 COMPLETED 27 — — Oct 17, 2022Dec 23, 2022May 18, 20231 Portugal
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Study Endpoints
Primary Endpoints
Incidence Rate of Treatment Emergent Serious Adverse Events (SAEs)
up to Week 52
Percentage of Participants With Smoking Abstinence From Weeks 3 to Week 6
Weeks 3 to 6

Smoking abstinence as verified by weekly expired carbon monoxide (CO) measurements ≤ 10 parts per million (ppm).

Percentage of Participants With Smoking Abstinence From Weeks 9 to Week 12
Weeks 9 to 12

Smoking abstinence as verified by weekly expired CO measurements ≤ 10 ppm.

Maximum Observed Plasma Concentration (Cmax)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Time of Maximum Observed Plasma Concentration (Tmax)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Time Point Prior to the First Quantifiable Concentration (Tlag)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Time of Last Quantifiable Observed Concentration (Tlast)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Area Under Plasma Concentration-Time Curve (AUC) Over the Dosing Interval (AUC0-τ)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
AUC From Time of Dosing (t=0h) to the Time of the Last Quantifiable Concentration (AUC0-t)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Total AUC Extrapolated to Infinity (AUC0-∞)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Percentage of AUC0-∞ Due to Extrapolation From the Time of the Last Quantifiable Concentration (Tlast) to Infinity (%AUCextrap)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Apparent Terminal Elimination Rate Constant (λz)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Apparent Terminal Elimination Half-Life (t1/2)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Apparent Clearance (CL/F)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Apparent Volume of Distribution (V/F)
Day 1 (Period 1) and Day 3 (Period 2): pre-dose and up to 24 hours post-dose
Pre-dose Plasma Concentration (Ctrough) for Dose 1, Dose 2 and Dose 3
Days 5 to 8 (Period 3): pre-dose
Cmax for Dose 1, Dose 2 and Dose 3
Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3)
Tmax for Dose 1, Dose 2 and Dose 3
Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3)
AUC0-τ for Dose 1, Dose 2 and Dose 3
Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3)

τ=5 h for Dose 1 and Dose 2 and τ=24 h for Dose 3

Concentration Over the Dosing Interval (Cτ) for Dose 1, Dose 2 and Dose 3
Days 5-7 (Period 3): predose, Day 8 (Period 3): pre-dose and up to 5 hours post-dose (Doses 1 and 2), predose and up to 24 hours post-dose (Dose 3)

τ=5 h for Dose 1 and Dose 2 and τ=24 h for Dose 3

Apparent Terminal Elimination Half-Life Interval (t1/2) post Dose 3
Day 8 (Period 3): up to 24 hours post-dose 3
Ratio of Cmax (R[Cmax])
Day 1 (Period 1) or Day 3 (Period 2), Day 8 (Period 3): Dose 1 (up to 5 hours post-dose)

Accumulation of cytisinicline following TID administration will be assessed by estimating R(Cmax), where R is the ratio of the pharmacokinetic parameter following administration of Dose 1 on Day 8 vs. single-dose administration under fasting conditions during Period 1 or 2.

Ratio of AUC0-τ (R[AUC0-τ])
Day 1 (Period 1) or Day 3 (Period 2), Day 8 (Period 3): Dose 1 (up to 5 hours post-dose)

Accumulation of cytisinicline following TID administration will be assessed by estimating R(AUC0-τ), where R is the ratio of the pharmacokinetic parameter following administration of Dose 1 on Day 8 vs. single-dose administration under fasting conditions during Period 1 or 2.

R(AUC0-τ/AUC0-∞)
Day 1 (Period 1) or Day 3 (Period 2), Day 8 (Period 3): Dose 1 (up to 5 hours post-dose)

Time invariance will be assessed as R(AUC0-τ/AUC0-∞), where AUC0-τ is estimated on Day 8 Dose 1 and AUC0-∞ is estimated for the single-dose under fasting conditions during Period 1 or 2.

Time to Steady State
Days 5 to 8 (Period 3): pre-dose

Time to steady state will be assessed by visual inspection of the Ctrough versus time plot.

Number of Participants With Treatment Emergent Adverse Events (AEs)
From first dose of study drug through the End-of Study Visit (Day 28-31)
Number of Participants With Clinically Significant Changes From Baseline in Electrocardiograms (ECG)
Baseline through Day 9
Number of Participants With Clinically Significant Changes From Baseline in Vital Signs
Baseline through Day 9
Number of Participants With Clinically Significant Changes From Baseline in Clinical Laboratory Tests
Baseline through Day 9
Predicted Placebo-Adjusted Change From Baseline in the Corrected QT Interval using Fridericia's Formula (QTcF) Interval (ΔΔQTcF)
Day -1 (first treatment period only) and on Day 1 (the day of dosing during each treatment period) from approximately 1 hour pre-dose on Day 1 through approximately 24 hours post dose on Day 1.
Secondary Endpoints
Incidence Rate of Related Treatment Emergent SAEs
up to Week 52
Incidence Rate of Treatment Emergent Adverse Events (TEAEs)
up to Week 52
Incidence Rate of Related TEAEs
up to Week 52
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Study Design & Arms
AllocationNA
MaskingNONE
ModelSINGLE_GROUP
PurposeTREATMENT
Treatment Arms
ArmTypeDescription
Cytisinicline 3 mg TIDEXPERIMENTALCytisinicline 3 mg TID for 52 weeks.
Placebo + Behavioral SupportPLACEBO_COMPARATOROne placebo tablet orally (PO) three times daily (TID) for 12 weeks plus behavioral support
6-Week Cytisinicline + 6-Week Placebo + Behavioral SupportEXPERIMENTALOne cytisinicline tablet PO TID for 6 weeks followed by one placebo tablet PO TID for 6 weeks plus behavioral support
12-Week Cytisinicline + Behavioral SupportEXPERIMENTALOne cytisinicline tablet PO TID for 12 weeks plus behavioral support
Cytisinicline + Placebo + Behavioral SupportEXPERIMENTALone cytisinicline tablet PO TID plus behavioral support for 6 weeks followed by one placebo tablet PO TID plus behavioral support for 6 weeks
Cytisinicline + Behavioral SupportEXPERIMENTALone cytisinicline tablet PO TID plus behavioral support for 12 weeks
Part 1: Cytisinicline 3 mg Once Daily (QD), FastingEXPERIMENTAL3 mg cytisinicline tablet administered in the morning, between 7:00 and 9:00 AM, in fasting conditions on Day 1 (Period 1) or Day 3 (Period 2). Participants will fast overnight for at least 10 hours before cytisinicline administration and will continue to fast for 4 hours after dosing.
Part 1: Cytisinicline 3 mg QD, FedEXPERIMENTAL3 mg cytisinicline tablet administered in the morning, between 7:00 and 9:00 AM, in fed conditions on Day 1 (Period 1) or Day 3 (Period 2). After an overnight fasting of at least 10 hours, participants will consume a standard high-fat-high-calorie meal within 30 minutes. Cytisinicline will be administered with 240 mL of water within 5 minutes after completion of the meal.
Part 2: Cytisinicline 3 mg 3 Times Daily (TID)EXPERIMENTAL3 mg cytisinicline tablet administered TID each day on Day 5 to 8 (Period 3) as follows: Dose 1 will be administered in the morning between 7:00 and 9:00 AM,; Dose 2 at 5 hours (±10 minutes) after Dose 1; Dose 3 at 5 hours (±10 minutes) after Dose 2. Cytisinicline will be administered on an empty stomach (cytisinicline given at least 2 hours before food or 1 hour after food).
Sequence 1EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) * Placebo (negative control) (8 placebo tablets) * Moxifloxacin 400 mg PO (positive control) (1 tablet) There will be a minimum 5 day washout between dosing periods.
Sequence 2EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) * Moxifloxacin 400 mg PO (positive control) (1 tablet) * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) * Placebo (negative control) (8 placebo tablets) There will be a minimum 5 day washout between dosing periods.
Sequence 3EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Placebo (negative control) (8 placebo tablets) * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) * Moxifloxacin 400 mg PO (positive control) (1 tablet) * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) There will be a minimum 5 day washout between dosing periods.
Sequence 4EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Moxifloxacin 400 mg PO (positive control) (1 tablet) * Placebo (negative control) (8 placebo tablets) * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) There will be a minimum 5 day washout between dosing periods.
Sequence 5EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) * Placebo (negative control) (8 placebo tablets) * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) * Moxifloxacin 400 mg PO (positive control) (1 tablet) There will be a minimum 5 day washout between dosing periods.
Sequence 6EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Placebo (negative control) (8 placebo tablets) * Moxifloxacin 400 mg PO (positive control) (1 tablet) * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) There will be a minimum 5 day washout between dosing periods.
Sequence 7EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) * Moxifloxacin 400 mg PO (positive control) (1 tablet) * Placebo (negative control) (8 placebo tablets) There will be a minimum 5 day washout between dosing periods.
Sequence 8EXPERIMENTALParticipants will receive the assigned study drug after an overnight fast on Day 1 during each of 4 periods in the following order: * Moxifloxacin 400 mg PO (positive control) (1 tablet) * Cytisinicline, 6 mg (therapeutic dose) (2 cytisinicline tablets+6 placebo tablets) * Placebo (negative control) (8 placebo tablets) * Cytisinicline, 24 mg (supratherapeutic dose) (8 cytisinicline tablets) There will be a minimum 5 day washout between dosing periods.
Interventions
NameTypeDescription
CytisiniclineDRUGfilm-coated oral tablets containing 3 mg cytisinicline
PlaceboDRUGfilm-coated oral tablets containing matched placebo
Behavioral supportBEHAVIORALBehavioral support sessions by a qualified study site staff member will be participant-driven and will include direct engagement with the subject about their attempt to quit smoking. Each session will last approximately 10 minutes.
MoxifloxacinDRUG400 mg tablets
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Eligibility Criteria
Age Range18 Years — N/A
SexALL
Healthy VolunteersNo
Study Sites29

Inclusion Criteria: 1. Prior participation in the ORCA-2, ORCA-3 or ORCA-V1 clinical studies. 2. Former ORCA-2/ORCA-3 and ORCA-V1 subjects who are current daily cigarette smokers and/or daily nicotine-containing electronic cigarette users. Amount of daily combustible and/or nicotine containing elec...

Countries:United StatesPortugal
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