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

• ClinicalTrials.gov Identifier: NCT04255875
• Recruitment Status: Active, not recruiting
• First Posted: February 5, 2020
• Last Update Posted: April 21, 2023
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Healthy; Sickle Cell Anemia	Biological: Placebo; Biological: PF-07209326	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Masking will only be applicable to Part 1 of the study where Healthy participants will be enrolled and randomized to receive either PF-07209326 or to placebo. In Part 2 of the study, all eligible SCD participants will receive PF-07209326 and no masking will be required.
• Primary Purpose: Basic Science
• Official Title: 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)
• Actual Study Start Date: February 5, 2020
• Estimated Primary Completion Date: July 6, 2023
• Estimated Study Completion Date: July 6, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Healthy Participants; Participants will receive single ascending doses of subcutaneous (SC) or intravenous PF-07209326	Biological: PF-07209326; Participants will receive SC or IV single ascending doses
Placebo Comparator: Placebo Healthy Participants; Participants will receive matching placebo	Biological: Placebo; Participants will receive matching placebo
Experimental: Treatment for SCD; Participants will receive a multiple dose of subcutaneous PF-07209326	Biological: PF-07209326; SCD participants will receive a multiple dose of subcutaneous PF-07209326

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 70 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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:

1. 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).
2. 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.
3. History of active or latent tuberculosis (TB) regardless of treatment or positive QuantiFeron TB test.

4. 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.
5. Participants with a history of allergic or anaphylactic reaction to therapeutic or diagnostic protein.
6. 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

1. Participants between the ages of 16 and 70 years old with a confirmed diagnosis of stable sickle cell disease (HbSS or HBS β0 thalassemia).
2. Medical history of ≥2 and ≤ 10 medical utilization VOCs in 12 months prior to screening.
3. ≥75% of daily ePRO diary completion, over a minimum of 14 days during the screening period.
4. 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.
5. Body Mass Index (BMI) ≤34.9 kg/m2 and weight ≥50 kg.

Exclusion Criteria for SCD Participants

1. 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.
2. 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.
3. History of cancer (other than cutaneous basal cell or carcinoma in-situ) in the previous 5 years.
4. 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.
5. History of active or latent tuberculosis (TB) regardless of treatment or positive QuantiFeron TB test.
6. Major surgery <3 months prior to baseline or planned significant medical procedures during the study.

7. 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.
8. Evidence or history of clinically significant orthostatic blood pressure changes.
9. 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.
10. Participants with a history of allergic or anaphylactic reaction to therapeutic or diagnostic protein.
11. Administration of voxelotor within 4 weeks prior to screening or planned use during the study.
12. Administration of crizanlizumab within 12 weeks prior to screening or planned use during the study.
13. Planned transfusion during the study.

Contacts and Locations

Locations

United States, Connecticut

New Haven Clinical Research Unit

New Haven, Connecticut, United States, 06511

United States, District of Columbia

Howard University College of Medicine

Washington, District of Columbia, United States, 20060

United States, Florida

Golisano Children's Hospital of Southwest Florida

Fort Myers, Florida, United States, 33908

Lee Health - Golisano Children's Hospital of Southwest Florida

Fort Myers, Florida, United States, 33908

Foundation for Sickle Cell Disease Research

Hollywood, Florida, United States, 33023

Foundation for Sickle Cell Disease Research

Hollywood, Florida, United States, 33024

United States, Georgia

Children's Healthcare of Atlanta - Egleston Hospital-Aflac Cancer and Blood Disorders Center

Atlanta, Georgia, United States, 30322

United States, Illinois

University of Illinois at Chicago Clinical Research Center

Chicago, Illinois, United States, 60612

University of Illinois at Chicago

Chicago, Illinois, United States, 60612

United States, Minnesota

Prism Research LLC dba Nucleus Network

Saint Paul, Minnesota, United States, 55114

United States, New York

Columbia University Medical Center - Herbert Irving Pavilion

New York, New York, United States, 10032

CUMC Research Pharmacy

New York, New York, United States, 10032

United States, Texas

UT Physicians Comprehensive Sickle Cell Center Houston

Houston, Texas, United States, 77004

Memorial Hermann clinical research unit

Houston, Texas, United States, 77030

UT Physicians Comprehensive Sickle Cell Center Houston

Houston, Texas, United States, 77030

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT04255875
• Other Study ID Numbers: C4071001
• First Posted: February 5, 2020
• Last Update Posted: April 21, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:

Safety; Tolerability; Single ascending dose; Multiple dose; Pharmacokinetics; Phase 1; First in human; First in patient

Additional relevant MeSH terms:

Anemia, Sickle Cell; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn