A Study of PF-07258669 In Healthy Adult Participants

Study Overview
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Brief Summary
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Part A of this study is to evaluate safety, tolerability, and pharmacokinetics (PK) of PF-07258669 after administration of multiple ascending oral doses to healthy adult participants. Optional cohorts of healthy adult Japanese participants and/or older adult participants may also be evaluated if results in other cohorts support further evaluation. Part B of this study is a 2-period, fixed-sequence, multiple-dose, open-label design to evaluate the effect of PF-07258669 on midazolam PK in healthy adult participants. Part B will be conducted if the results of Part A support further evaluation of PF-07258669.

Official Title
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A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACOKINETIC INTERACTION WITH MIDAZOLAM OF MULTIPLE ASCENDING ORAL DOSES OF PF-07258669 IN HEALTHY NON-JAPANESE AND JAPANESE ADULT PARTICIPANTS

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: PF-07258669
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For optional cohort of older adult participants only: Male participants and female participants of non childbearing potential must be 65 to 90 years of age, inclusive, at the time of signing the ICD (informed consent document). Attempts will be made to ensure that the age composition of this cohort (eg, approximately 70% of participants ≥70 years of age) is comparable to that of the anticipated patient population in later clinical studies. Female participants of nonchildbearing potential and male participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring. For optional cohort of older adult participants only: Participants must be in a stable condition at admission. These participants must be in reasonably good health as determined by the investigator based on a detailed medical history, full physical examination, vital signs assessments, 12-lead ECG (electrocardiogram), and clinical laboratory tests. Participants with mild, chronic, stable disease (eg, controlled hypertension, noninsulin dependent diabetes, osteoarthritis) may be enrolled if deemed medically prudent by the investigator. Participants who are willing to avoid direct sunlight exposure or any high intensity ultraviolet light exposure from admission to the follow-up contact and to apply sunscreen/lotion with a high sun protection factor and to wear eye protection, as appropriate. Body mass index (BMI) of 17.5 to 28.5 kg/m2; and a total body weight >50 kg (110 lb). For optional cohort of older adult participants only: BMI of 17.5 to 32.4 kg/m2; and a total body weight >50 kg (110 lbs). Efforts will be made to enroll at least 3 older adult participants with BMI <25 kg/m2, if feasible. Japanese participants only: Participants enrolling as Japanese must have 4 biological Japanese grandparents who were born in Japan. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine (including, but not limited to, thyroid disease, diabetes insipidus), pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric (including, but not limited to, primary polydipsia, obsessive compulsive disorder, anxiety disorder, schizophrenia), neurological (including, but not limited to, seizure disorder, traumatic brain injury), immunodeficiency (including, but not limited to, severe infection that required ICU admission, prolonged hospitalization, or prolonged treatment) or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing), as well as presence of clinical laboratory abnormalities. For optional cohort of older adult participants only: Participants with chronic conditions (eg, hypertension) that are controlled by either diet or stable doses of medications may be included. Recent evidence (ie, within previous 6 months) or history of unstable disease or moderate to severe conditions which would, in the investigator's opinion, interfere with the study evaluations or have an impact on the safety of participants. History of symptomatic orthostatic hypotension or symptomatic bradycardia. History of eating disorders (eg, anorexia or bulimia nervosa, binge-eating disorder, avoidant/restrictive food intake disorder). 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. For optional cohort of older adult participants only: Participants taking daily prescription or non-prescription medications (that are not moderate or strong cytochrome P450 (CYP3A) inducers or inhibitors) for management of acceptable chronic medical conditions are to be on a stable dose, as defined by no change in dose for the 28 days or 5 half-lives (whichever is longer) before the screening visit. Use of stable concomitant mediations noted above that are CYP3A substrates may be restricted. All medications must be reviewed on a case-by-case basis by the investigator and approved by the sponsor during the screening period for eligibility purposes. Use of moderate or strong cytochrome P450 3A (CYP3A) inhibitors or inducers within 28 days or 5 half-lives (whichever is longer) prior to first dose of study intervention. 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). Fasting serum triglycerides >2× ULN (upper limit of normal).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07258669 and Placebo (Cohort 1)<br>Dose level 1: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Carbohydrate High Calorie (HCHC) | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 2)<br>Dose level 2: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: HCHC | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 3)<br>Dose level 3: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: HCHC | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 4)<br>Dose level 4: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: Standard Diet (SD) | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 5)<br>Dose level 5: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 6)<br>Multiple dose administration of PF-07258669 and placebo over 14 days in Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: Midazolam with and without PF-07258669 (Cohort 8)<br>Drug-drug interaction assessment of pharmacokinetics interaction in PF-07258669 and midazolam Dietary allocation: SD | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Midazolam<br>* Single doses of Midazolam will be administered as oral solution alone and in combination with PF-07258669<br>|
| Experimental: PF-07258669 and Placebo (Cohort 7)<br>Multiple dose administration of PF-07258669 and placebo over 14 days in older adult participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 9)<br>Dose level 6: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 10)<br>Dose level 7: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 11)<br>Dose level 8: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: SD | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 12)<br>Dose Level 9: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Fat High Calorie (HFHC) | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|
| Experimental: PF-07258669 and Placebo (Cohort 13)<br>Dose Level 10: Multiple dose administration of PF-07258669 and placebo over 14 days in non-Japanese participants; 8 participants will receive PF-07258669 and 2 will receive placebo Dietary allocation: High Fat High Calorie (HFHC) | Drug: PF-07258669<br>* PF-07258669 will be administered as tablets; every 8 hour (Q8H) or every 12 hour (Q12H) over 14 days<br>Drug: Placebo<br>* Placebo will be administered as tablets; Q8H or Q12H over 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A:Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) |  | Baseline up to 35 days after last dose of study intervention (approximately 11 weeks). | 
| Part A: Number of Participants With Clinical Laboratory Abnormalities |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks). | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in Vital Signs |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks). | 
| Part A: Number of Participants With Cardiac Rhythms of Potential Clinical Concern Assessed By Telemetry |  | 0 to 8 hours post-dose on Day 1 | 
| Part A: Number of Participants With Cardiac Rhythms of Potential Clinical Concern Assessed By Telemetry |  | 0 to 8 hours post-dose on Day 7 | 
| Part A: Number of Participants With Cardiac Rhythms of Potential Clinical Concern Assessed By Telemetry |  | 0 to 8 hours post-dose on Day 14 | 
| Part A: Number of Participants With Change From Baseline in Electrocardiogram (ECG) Findings |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks). | 
| Part A: Number of Participants With Clinically-Significant Change From Baseline in Physical Examination Findings |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks). | 
| Part A: Number of Participants With Clinically-Significant Change From Baseline in Neurological Examination Findings |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks). | 
| Part A: Number of Participants With Positive Response on Columbia Suicide Severity Rating Scale (C-SSRS) on Day 14 | C-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced following: completed suicide; suicide attempt (response of Yes on actual attempt); preparatory acts toward imminent suicidal behavior (Yes on preparatory acts or behavior, aborted attempt or interrupted attempt), suicidal ideation (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent). In this outcome, number of participants with positive response (response of yes) to suicidal behavior, ideation or any self-injurious behavior, at Day 14 were reported. | Day 14 | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in 24-Hour Fluid Intake |  | 0 to 24 hours on Day -1 | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in 24-Hour Fluid Intake |  | 0 to 24 hours on Day 7 | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in 24-Hour Fluid Intake |  | 0 to 24 hours on Day 14 | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in 24-Hour Urine Output |  | 0 to 24 hours on Day -1 | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in 24-Hour Urine Output |  | 0 to 24 hours on Day 7 | 
| Part A: Number of Participants With Clinically Significant Change From Baseline in 24-Hour Urine Output |  | 0 to 24 hours on Day 14 | 
| Part B: Maximum Observed Plasma Concentration (Cmax) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 1/Day 1 | 
| Part B: Maximum Observed Plasma Concentration (Cmax) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 2/Day 2 | 
| Part B: Maximum Observed Plasma Concentration (Cmax) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 2/Day10 | 
| Part B: Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 1/Day 1 | 
| Part B: Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 2/Day 2 | 
| Part B: Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 2/Day10 | 
| Part B: Area under the plasma concentration-time curve from time 0 to Extrapolated Infinite Time (AUCinf) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 1/Day 1 | 
| Part B: Area under the plasma concentration-time curve from time 0 to Extrapolated Infinite Time (AUCinf) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 2/Day 2 | 
| Part B: Area under the plasma concentration-time curve from time 0 to Extrapolated Infinite Time (AUCinf) of Midazolam |  | Time Frame: predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Period 2/Day10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum Observed Plasma Concentration (Cmax) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 1 | 
| Part A: Maximum Observed Plasma Concentration (Cmax) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 14 | 
| Part A: Dose Normalized Maximum Observed Plasma Concentration (Dose-Normalized Cmax) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 1 | 
| Part A: Dose Normalized Maximum Observed Plasma Concentration (Dose-Normalized Cmax) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 14 | 
| Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to Dosing Interval (tau) (AUCtau) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 1 | 
| Part A: Area Under the Plasma Concentration-Time Curve From Time 0 to Dosing Interval (tau) (AUCtau) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 14 | 
| Part A: Dose Normalized Area Under the Curve from Time 0 to Dosing Interval (tau) (Dose-Normalized AUCtau) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 1 | 
| Part A: Dose Normalized Area Under the Curve from Time 0 to Dosing Interval (tau) (Dose-Normalized AUCtau) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 14 | 
| Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 1 | 
| Part A: Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-07258669 |  | Time Frame: predose, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours post dose on Day 14 | 
| Part A: Amount of PF-0728669 Excreted Unchanged in Urine Over the Dosing Interval Tau (Aetau) |  | On Day 14, urine collection for PK to occur over 0-tau, according to dosing frequency (ie, 0-8 hours for 8 hour dosing interval; 0-12 hours for 12 hour dosing interval) | 
| Part A: Percentage of Dose of PF-07258669 Excreted Unchanged in the Urine Over the Dosing Interval Tau (Aetau%) |  | On Day 14, urine collection for PK to occur over 0-tau, according to dosing frequency (ie, 0-8 hours for 8 hour dosing interval; 0-12 hours for 12 hour dosing interval) | 
| Part A: Renal Clearance of PF-07258669 |  | On Day 14, urine collection for PK to occur over 0-tau, according to dosing frequency (ie, 0-8 hours for 8 hour dosing interval; 0-12 hours for 12 hour dosing interval) | 
| Part B: Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) |  | Baseline up to 35 days after last dose of study intervention (approximately 10 weeks) | 
| Part B: Number of Participants With Clinically Significant Change From Baseline in Vital Signs |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks) | 
| Part B: Number of Participants With Oxygen Saturation Levels of Potential Clinical Concern |  | 0 to 6 hours post-dose on Period 1/Day 1 | 
| Part B: Number of Participants With Oxygen Saturation Levels of Potential Clinical Concern |  | 0 to 6 hours post-dose on Period 2/Day 2 | 
| Part B: Number of Participants With Oxygen Saturation Levels of Potential Clinical Concern |  | 0 to 6 hours post-dose on Period 2/Day 10 | 
| Part B: Number of Participants With Change From Baseline in Electrocardiogram (ECG) Findings |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks) | 
| Part B: Number of Participants With Clinical Laboratory Abnormalities |  | Baseline up to 10 days after last dose of study intervention (approximately 7 weeks) | 
| Part B: Number of Participants With Clinically-Significant Change From Baseline in Physical Examination Findings |  | Baseline up to 35 days after last dose of study intervention (approximately 10 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-07258669, multiple dose, melanocortin-4 receptor, MC4R, healthy participants, safety, tolerability, pharmacokinetics