Safety Study of Cytisinicline in Adult Combustible And/or E-cigarette Smokers

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 smokersand/or daily nicotine-containing electronic cigarette users. Amount of dailycombustible and/or nicotine containing electronic cigarette use at baseline isdetermined by subject self-report.

3. At Screening, subjects must have expired carbon monoxide (CO) ≥10 ppm ifself-reporting as smokers or ≥30 ng/mL cotinine using a point-of-care cotinine oralfluid screening device if self-reporting as users of nicotine containing electroniccigarettes.

4. Willing to initiate cytisinicline treatment on the day after enrollment and set aquit date within 14 days of starting treatment.

5. Willing to actively participate in the study's cessation behavioral support providedthroughout the study.

6. Able to fully understand study requirements, willing to participate, and comply withdosing schedule.

7. Sign the Informed Consent Form.

Exclusion Criteria:

1. Known hypersensitivity to cytisinicline or any of the excipients.

2. Clinically significant abnormal screening serum chemistry or hematology values.

3. Clinically significant abnormal screening 12-lead ECG determined after minimum of 5minutes in supine position (ie, requiring treatment or further assessment).

4. Recent history (within 3 months prior to screening) of acute myocardial infarction,unstable angina, stroke, cerebrovascular incident or hospitalization for congestiveheart failure.

5. Current uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolicblood pressure ≥100 mmHg).

6. Currently psychotic or having had a psychotic event within 3 months prior toscreening; currently having suicidal ideation or risk for suicide (corresponding toquestion 4 or 5 on the screening C-SSRS OR "Yes" to any suicidal behavior questionon the screening C-SSRS with clear suicidal intent or previous attempt); or currentsymptoms of moderate to severe depression (depression score ≥11 on the HADS) atscreening. If any subject becomes psychotic during the study, they must be removedfrom cytisinicline treatment and/or additional study visits.

7. Severe renal impairment defined as a creatinine clearance (CrCl) <60 mL/min onscreening lab (estimated with the Cockroft-Gault equation).

8. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartateaminotransferase (AST) >2.0 x the upper limit of normal (ULN) on screening lab.

9. Women who are pregnant or breast-feeding.

10. Female subjects of childbearing potential who do not agree to use acceptable methodsof birth control during the study. Acceptable methods of birth control include:

• True abstinence: When this is in line with the preferred and usual lifestyle ofthe subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception].

• Barrier methods:

• diaphragm

• cervical cap

• contraceptive sponge

• Hormonal methods:

• Oral contraceptives

• Vaginal ring such as NuvaRing

• Skin patch such as Xulane

• Injection such as Depro-Provera

• Implantable rod such as Nexplanon

11. Participation in a clinical study with an investigational drug in the 4 weeks priorto enrollment.

12. Any other reason that the investigator views the subject should not participate orwould be unable to fulfill the requirements for the study.