A Drug-Drug Interaction Study Between PF-06882961 and PF-06865571 in Healthy Adult Participants and Overweight Adults or Adults With Obesity Who Are Otherwise Healthy
Condition: Healthy Volunteer
MeSH terms: Overweight
Intervention: PF-06882961 followed by PF-06882961/PF-06865571; PF-06882961/PF-06865571 followed by PF-06882961; PF-06882961 + PF-06865571
Intervention description: Treatment A - PF-06882961 20 mg single dose followed by Treatment B - PF-06882961 20 mg single dose plus PF-06865571 300 mg single dose. There will be a washout interval between periods of at least 3 days.; Treatment B - PF-06882961 20 mg single dose plus PF-06865571 300 mg single dose followed by Treatment A - PF-06882961 20 mg single dose. There will be a washout interval between periods of at least 3 days.; Period 1: PF-06865571 300 mg single dose (Day 1), Period 2: PF-06882961 10 mg twice daily dose titration up to 200 mg twice daily dosing (Days 3-46), Period 3: PF-06865571 300 mg single dose (Day 47) and PF-06882961 200 mg twice daily dosing (Days 47-48), Period 4: PF-06865571 300 mg twice daily dosing and PF-06882961 200 mg twice daily dosing (Days 49-62)
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Masking description: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This study will be conducted in 2 parts. Part A will investigate the potential effect of
      PF-06865571 on the pharmacokinetics (PK) of PF-06882961 in healthy adult participants. Part B
      will evaluate the effect of PF-06882961 on the PK of PF-06865571, as well as the effect of
      PF-06865571 on the PK of PF-06882961 in overweight adults or adults with obesity who are
      otherwise healthy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male and female participants must be 18 to 65 years of age, inclusive, at the time of
             signing the ICD.

             Women can be of child-bearing potential, however, cannot be pregnant, breastfeeding,
             or planning to become pregnant while participating in the study.

          2. Male and female participants who are overtly healthy (other than being overweight or
             obese in Part B only) as determined by medical evaluation including medical history,
             physical examination, and laboratory tests.

          3. Participants who are willing and able to comply with all scheduled visits, treatment
             plan, laboratory tests, lifestyle considerations, and other study procedures.

          4. BMI and total body weight:

             Part A: BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb); Part B:
             BMI ≥25 kg/m2 and not more than 40 kg/m2 at Screening; stable body weight, defined as
             <5 kg change (per participant report) for 90 days before Screening.

          5. Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the ICD and in this protocol.

        Exclusion Criteria

          1. Evidence or history of clinically significant hematological, renal, endocrine,
             pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or
             allergic disease (including drug allergies, but excluding untreated, asymptomatic,
             seasonal allergies at the time of dosing).

          2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy,
             bariatric surgery, active inflammatory bowel disease, or an intestinal resection).

          3. Other medical or psychiatric condition including recent (within the past year) or
             active suicidal ideation/behavior or laboratory abnormality or other conditions or
             situations related to COVID-19 pandemic (eg, contact with positive case, residence or
             travel to an area with high incidence) that may increase the risk of study
             participation or, in the investigator's judgment, make the participant inappropriate
             for the study.

          4. Known intolerance or hypersensitivity to GLP-1 receptor agonists.

          5. Known intolerance or hypersensitivity to DGAT2 inhibitors.

          6. Diagnosis of type 1 or type 2 diabetes mellitus or secondary forms of diabetes at
             screening. Note: women with prior diagnoses of gestational diabetes during pregnancy
             only are eligible if they meet the other eligibility criteria.

          7. History of myocardial infarction, unstable angina, arterial revascularization, stroke,
             New York Heart Association Functional Class II-IV heart failure, or transient ischemic
             attack within 6 months of Screening.

          8. Any malignancy not considered cured (except basal cell carcinoma and squamous cell
             carcinoma of the skin); a study participant is considered cured if there has been no
             evidence of cancer recurrence in the previous 5 years (from Screening).

          9. Personal or family history of medullary thyroid carcinoma or multiple endocrine
             neoplasia syndrome type 2, or study participants with suspected medullary thyroid
             carcinoma per the investigator's judgment.

         10. Acute pancreatitis or history of chronic pancreatitis.

         11. Symptomatic gallbladder disease.

         12. Medical history or characteristics suggestive of genetic or syndromic obesity or
             obesity induced by other endocrinological disorders (eg, Cushing Syndrome).

         13. History of major depressive disorder or history of other severe psychiatric disorders
             (eg, schizophrenia or bipolar disorder) within the last 2 years from screening.

         14. Known medical history of active liver disease (other than non-alcoholic hepatic
             steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis,
             alcoholic liver disease, primary sclerosing cholangitis, autoimmune hepatitis, overlap
             syndrome, or prior known drug-induced liver injury.

         15. History of HIV infection.

         16. Any lifetime history of a suicide attempt.

         17. Use of prescription or nonprescription drugs and dietary and herbal supplements within
             7 days or 5 half-lives (whichever is longer) prior to the first dose of study
             intervention.

         18. Prohibited prior/concomitant medication as per protocol.

         19. Previous administration with an investigational drug within 30 days (or as determined
             by the local requirement) or 5 half-lives preceding the first dose of study
             intervention used in this study (whichever is longer). An emergency use authorized or
             approved COVID-19 vaccine is considered a concomitant medication.

         20. Known prior participation in a clinical trial with PF-06882961 or PF-06865571.

         21. Part B only: A Patient Health Questionnaire (PHQ-9) score ≥15 obtained at Screening or
             Day -1.

         22. Part B only: Response of "yes" to question 4 or 5, or on any behavioral question on
             the C-SSRS at Screening or Day -1.

         23. A positive urine drug test.

         24. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least
             5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), the
             BP should be repeated 2 more times and the average of the 3 BP values should be used
             to determine the participant's eligibility.

         25. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may
             affect participant safety or interpretation of study results (eg, baseline QTc
             interval >450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial
             infarction, ST-T interval changes suggestive of myocardial ischemia, second- or
             third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the
             baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected
             using the Fridericia method and the resulting QTcF should be used for decision making
             and reporting. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be
             repeated 2 more times and the average of the 3 QTc or QRS values should be used to
             determine the participant's eligibility. Computer-interpreted ECGs should be overread
             by a physician experienced in reading ECGs before excluding participants.

         26. A positive COVID-19 test at or after screening.

         27. Participants with ANY of the following abnormalities in clinical laboratory tests at
             screening, as assessed by the study-specific laboratory and confirmed by a single
             repeat test, if deemed necessary: HbA1c ≥6.5%. AST or ALT > ULN. Total bilirubin level
             > ULN; participants with a history of Gilbert's syndrome may have direct bilirubin
             measured and are eligible for this study provided the direct bilirubin level is ≤ ULN.

             TSH > ULN or < LLN. Serum calcitonin > ULN. Amylase or lipase > ULN. Fasting blood
             glucose ≥126 mg/dL. Fasting triglycerides >200 mg/dL. INR > ULN. PLT < LLN. eGFR <80
             mL/min/1.73 m2 as calculated by the CKD-EPI equation. Positive testing for HIV,
             HepBsAg, or HCVAb. Study participants positive for HCVAb are to be excluded unless
             known to have been treated with a known curative therapy and negative for HCV RNA.
             Hepatitis B vaccination is allowed.

         28. Participation in a formal weight reduction program (eg, Weight Watchers) within 90
             days prior to Screening.

         29. History of alcohol abuse or binge drinking and/or any other illicit drug use or
             dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5
             (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule,
             alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1
             ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).

         30. Current use of tobacco or nicotine containing products in excess of the equivalent of
             5 cigarettes per day.

         31. Known or suspected illicit drug use.

         32. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more
             within 60 days prior to dose randomization (Day -1).

         33. History of sensitivity to heparin or heparin-induced thrombocytopenia if Hep-lock is
             used for IV blood draw.

         34. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
             section of this protocol.

         35. Investigator site staff or Pfizer employees directly involved in the conduct of the
             study, site staff otherwise supervised by the investigator, and their respective
             family members.