Dose Escalation Study of PF-07209326 in Healthy Participants and Participants With Sickle Cell Disease

Study Overview
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Brief Summary
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This Phase 1 first-in-human, first-in-patient, single ascending dose and multiple dose study will be a randomized, double-blind, placebo-controlled investigation of the safety, tolerability, and pharmacokinetics of PF-07209326 in healthy participants and participants with sickle cell disease.

Detailed Description
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Part 1 will evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of single ascending doses of PF-07209326 delivered by subcutaneous injection or intravenous delivery in healthy volunteer participants. After establishing the safety and tolerability in healthy participants, Part 2 will evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of subcutaneously delivered multiple dose of PF-07209326 in participants with sickle cell disease.

Official Title
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A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED EVALUATION OF SINGLE DOSES OF PF-07209326 IN HEALTHY PARTICIPANTS (SAFETY, TOLERABILITY, AND PHARMACOKINETICS [PK]) FOLLOWED BY AN OPEN LABEL, REPEAT DOSE EVALUATION IN SICKLE CELL DISEASE PARTICIPANTS (SAFETY, TOLERABILITY, PK AND EFFICACY)

Conditions
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Healthy, Sickle Cell Anemia

Intervention / Treatment
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* Biological: Placebo
* Biological: PF-07209326
* Biological: PF-07209326


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Health Participants: 1. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs). Exclusion Criteria Healthy Participants: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, immunocompromised (or known disorder of the immune system), cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing). History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody (HCVAb). Hepatitis B vaccination is allowed. History of active or latent tuberculosis (TB) regardless of treatment or positive QuantiFeron TB test. Participants with any of the following acute or chronic infections or infection history: Any infection requiring treatment within 2 weeks prior to the screening visit. Any infection requiring hospitalization, parenteral antimicrobial therapy within 30 days of the first dose of investigational product. Any infection judged to be an opportunistic infection, within the past 6 months of the first dose of the investigational product. Known active or history of frequent bacterial, viral, fungal, mycobacterial or other infections as determined by the PI. Participants with a fever within the last 7 days prior to dosing. Participants with a history of allergic or anaphylactic reaction to therapeutic or diagnostic protein. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Inclusion Criteria for SCD Participants Participants between the ages of 16 and 70 years old with a confirmed diagnosis of stable sickle cell disease (HbSS or HBS β0 thalassemia). Medical history of ≥2 and ≤ 10 medical utilization VOCs in 12 months prior to screening. ≥75% of daily ePRO diary completion, over a minimum of 14 days during the screening period. Fully vaccinated for COVID-19 in accordance with the Center for Disease Control guidance prior to Screening or must be negative for SARS-CoV-2 by polymerase chain reaction (PCR) within 72 hours of the Day 1 visit. Body Mass Index (BMI) ≤34.9 kg/m2 and weight ≥50 kg. Exclusion Criteria for SCD Participants Evidence of ongoing uncontrolled clinically significant co-morbidity (e.g. intercurrent events that result in signs symptoms that have an adverse impact on the respective individual's usual function) hematological (non-SCD), renal, endocrine, pulmonary, gastrointestinal, cardiovascular (including stroke within 2 years prior to screening), hepatic, psychiatric or neurological. Evidence or history of cardiac disease includes myocardial infarction, clinically significant cardiac arrhythmia (eg, atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia), left ventricular failure, unstable angina, and coronary artery bypass grafting. History of cancer (other than cutaneous basal cell or carcinoma in-situ) in the previous 5 years. Active infection with Hepatitis B or C or HIV. Individuals seropositive for infection with Hepatitis C must be negative for viral RNA by PCR on at least 2 determinations. History of active or latent tuberculosis (TB) regardless of treatment or positive QuantiFeron TB test. Major surgery <3 months prior to baseline or planned significant medical procedures during the study. Participants with any of the following acute or chronic infections or infection history: Any infection requiring systemic treatment within 2 weeks prior to the screening visit. Any infection requiring hospitalization, parenteral antimicrobial therapy within 30 days of the first dose of investigational product. Any infection judged to be an opportunistic infection, within the past 6 months of the first dose of the investigational product. Known active or history of frequent viral, fungal or other infections as determined by the Investigator. Participants with a fever within the last 7 days prior to dosing. Evidence or history of clinically significant orthostatic blood pressure changes. Other acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Participants with a history of allergic or anaphylactic reaction to therapeutic or diagnostic protein. Administration of voxelotor within 4 weeks prior to screening or planned use during the study. Administration of crizanlizumab within 12 weeks prior to screening or planned use during the study. Planned transfusion during the study.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Healthy Participants<br>Participants will receive single ascending doses of subcutaneous (SC) or intravenous PF-07209326 | Biological: PF-07209326<br>* Participants will receive SC or IV single ascending doses<br>|
| Placebo Comparator: Placebo Healthy Participants<br>Participants will receive matching placebo | Biological: Placebo<br>* Participants will receive matching placebo<br>|
| Experimental: Treatment for SCD<br>Participants will receive a multiple dose of subcutaneous PF-07209326 | Biological: PF-07209326<br>* SCD participants will receive a multiple dose of subcutaneous PF-07209326<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency, severity and causal relationship of treatment emergent adverse events (TEAEs) and withdrawals due to TEAEs | Frequency, severity and causal relationship of treatment emergent adverse events (TEAEs) and withdrawals due to TEAEs | Day 1 up to Day 85 (SAD) or Day 113 (MD) | 
| Percentage of subjects with laboratory abnormalities | Percentage of subjects with laboratory abnormalities | Day 1 up to Day 85 (SAD) or Day 113 (MD) | 
| Number of subjects with change from baseline in vital signs | blood pressure, pulse rate, temperature, respiration rate | Day 1 up to Day 85 (SAD) or Day 85 (MD) | 
| Number of subjects with change from baseline in electrocardiogram (ECG) parameters | Number of subjects with change from baseline in electrocardiogram (ECG) parameters | Day 1 up to Day 85 (SAD) or Day 85 (MD) | 
| Percentage of subjects with injection site reactions | Percentage of subjects with injection site reactions | Day 1 up to Day 11 post (SAD) Day 1 up to Day 85 (MD) | 
| Percentage of subjects with infusion site reactions | Percentage of subjects with infusion site reactions | Day 1 up to Day 11 post each dose (SD) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SAD: Single Dose PK /Cmax | Maximum serum concentration | Day 1 up to Day 85 | 
| SAD: Single Dose PK / DN Cmax | Dose normalized Cmax | Day 1 up to Day 85 | 
| SAD: Single Dose PK / Tmax | Time for Cmax | Day 1 up to Day 85 | 
| SAD: Single Dose PK / AUClast | Area under the serum concentration time profile from time zero to the time of the last quantifiable concentration. | Day 1 up to Day 85 | 
| SAD: Single Dose PK / DN AUClast | Dose normalized AUClast | Day 1 up to Day 85 | 
| SAD: Single Dose PK / AUCinf | Area under the serum concentration time profile from time zero to infinity. | Day 1 up to Day 85 | 
| SAD: Single Dose PK / DN AUCinf | Dose normalized AUCinf. | Day 1 up to Day 85 | 
| SAD: Single Dose PK / t½ | Terminal half life | Day 1 up to Day 85 | 
| SAD: Single Dose PK / CL (IV only) | Clearance | Day 1 up to Day 85 | 
| SAD: Single Dose PK / CL/F (SC only) | Apparent clearance | Day 1 up to Day 85 | 
| SAD: Single Dose PK / Vss (IV only) | Volume of distribution at steady state | Day 1 up to Day 85 | 
| SAD: Single Dose PK / Vz/F (SC only) | Apparent volume of distribution at steady state | Day 1 up to Day 85 | 
| SAD: Single Dose PK / F (SC only) | Apparent bioavailability | Day 1 up to Day 85 | 
| MD: AUCtau | Area under the curve over the dosing interval tau (1 week) after the first and last doses | Day 1 up to Day 22 | 
| SAD:ADA and/or NAb | Frequency of anti-drug antibody (ADA) and/or neutralizing antibody (NAb) productions | Day 1 up to Day 85 | 
| MD:ADA and/or NAb | Frequency of anti-drug antibody (ADA) and/or neutralizing antibody (NAb) productions | Day 1 up to Day 113 | 
| Patient-reported VOC event rate and VOC day rate | Efficacy in SCD participants based on an electronic patient reported outcome. | Day 1 to 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Multiple dose, Pharmacokinetics, First in human, First in patient, Tolerability, Single ascending dose, Safety