Clinical trial NCT06349473: A Study of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SR604 in Two Participants Groups (Part A: Healthy Participants, and Part B: Participants With Hemophilia A or Hemophilia B)
Official title: A Phase 1 Single and Multiple Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SR604 in Healthy Participants (Part A) and the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of SR604 in Participants With Hemophilia A or Hemophilia B (Part B)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Healthy Participants
Hemophilia A
Hemophilia B
Keywords: Single ascending dose
Multiple ascending dose
Factor IX
Factor VIII
Lead sponsor: Equilibra Bioscience LLC
Sponsor class: INDUSTRY
First posted: 2024-04-05
Enrollment: 36
Sex: MALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) of SR604 in healthy participants (Part A) and to evaluate the safety, tolerability, PK, PD, and efficacy of SR604 in participants with Hemophilia A or Hemophilia B, with or without inhibitors (Part B).

Detailed description: This is a first-in-human (FIH) study to be conducted with SR604. The study will enroll healthy participants (Part A) and participants with Hemophilia A or Hemophilia B (Part B).

In Part A (single ascending dose \[SAD\]): Healthy participants will be randomized in a 2:1 ratio in each of the 3 to 4 (Cohort 4 is optional) sequential cohorts. All cohorts will include participants receiving active treatment with SR604 and the other participant receiving matching placebo.

In Part B (multiple ascending dose \[MAD\]): Participants with Hemophilia A or Hemophilia B, with or without inhibitors, will be enrolled in 4 cohorts with four dose levels and is planned to receive SR604 subcutaneously.

The overall duration of study participation will be approximately 3 months.

Eligibility criteria: Key Inclusion Criteria:

Part A:

* Body mass index between 18 and 30 kilograms per meter square (kg/m\^2), inclusive, and weighs greater than or equal to (\>=) 50 kilograms (kg), less than or equal to (\<=) 90 kg.
* No clinically significant findings on medical examination, including physical examination, 12-lead electrocardiogram, and clinical laboratory tests.
* Sexually active men must commit to use an effective method of birth control while taking the study intervention and for 90 days after the dose of study intervention.

Part B:

* Participants must have one of the following bleeding disorders: Severe congenital Hemophilia A and Severe and/or moderately severe congenital Hemophilia B.
* Participants whose bleeding is not well controlled on their current treatment regimen.
* Medical records documenting a minimum of 2 years of bleeding event history.
* Willing to undergo a weaning period from prior Hemophilia A or Hemophilia B treatment or prophylaxis.
* Sexually active men must commit to use an effective method of birth control while taking the study intervention and for 90 days after the dose of study intervention.

Key Exclusion Criteria:

Part A:

* Participant has clinically significant history or evidence of cardiovascular, respiratory (including all chronic lung diseases), hepatic, renal, gastrointestinal, endocrine, neurological, immunological, bleeding, or psychiatric disorder(s).
* Participant has a mean pulse less than (\<) 40 or greater than (\>) 90 beats per minute (bpm), mean systolic blod pressure (BP) \< 90 millimeter of mercury (mmHg) or \> 140 mmHg, or mean diastolic BP \< 50 mmHg or \> 90 mmHg at the screening visit.
* Participant has a mean corrected QT corrected for heart rate by Fridericia's formula (QTcF) of \> 450 msec at the Screening Visit.
* Participant has had injury, trauma, and/or major surgery within 3 months before Screening, or is planned to undergo surgery during the study.
* Participant has received vaccination within 14 days before the dose of study intervention or has a vaccination planned during the study.
* History of one or more of the following in participants and/or family members:

  1. Factor V (FV) Leiden mutation.
  2. Activated protein C (APC) resistant.
  3. Protein C (PC) or protein S (PS) deficiency.
  4. Prothrombin 20210 mutation;
  5. Antithrombin III (ATIII) deficiency.
* History of clinically significant intracranial hemorrhage, pneumonia, chronic liver disease, liver or kidney transplants, or malignant diseases.
* Any medical condition (eg, diabetes, obesity.) which, in the Investigator's opinion, could compromise participant safety, interfere with study intervention metabolism, or put the study outcome at undue risk. Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant or could prevent, limit or confound protocol-specified assessments.
* Participants with a history of all types of thrombosis, including any arterial and/or venous thrombosis, superficial thrombophlebitis, or embolism. Additionally, participants with a history of thrombotic microangiopathy, stroke, and transient ischemic attack (TIA), or abnormal findings in any prior laboratory thrombophilia evaluation will be excluded.

Part B:

* Participants with a history of all types of thrombosis, including any arterial and/or venous thrombosis, superficial thrombophlebitis, or embolism. Additionally, participants with a history of thrombotic microangiopathy, stroke, and TIA, or abnormal findings in any prior laboratory thrombophilia evaluation will be excluded.
* History of one or more of the following in participants and/or family members:

  1. FV Leiden mutation.
  2. APC resistant.
  3. PC or PS deficiency.
  4. Prothrombin 20210 mutation.
  5. ATIII deficiency.
* Impaired cardiac function or clinically significant cardiac disease, including any of the following:

  1. Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (New York Heart Association Grade \>=2), left ventricular ejection fraction \< 50% as determined by multiple gated acquisition or echocardiogram, or clinically significant arrhythmia.
  2. QTcF \> 450 ms ECG or congenital Long QT Syndrome at the Screening Visit.
  3. Acute myocardial infarction or unstable angina pectoris \< 3 months prior to study entry.
* Uncontrolled hypertension (systolic BP \> 150 mmHg and diastolic BP \> 100 mmHg), a history of hypertension crisis, or a history of hypertensive encephalopathy.
* Participant with the following laboratory abnormalities:

  1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 1.5 × upper limit of normal (ULN);
  2. Total bilirubin ˃3.0 × ULN and direct bilirubin ˃1.5 × ULN (unless due to Gilbert's syndrome).
* Calculated creatinine clearance ˂ 60 mL/min using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at the Screening Visit.
* Participant has positive test result for human immunodeficiency virus (HIV) antibody. a) If participants test positive for hepatitis B core antibody (HBcAb), additional tests including hepatitis B surface antibody, hepatitis B surface antigen (HBsAg), and hepatitis B viral deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) will be conducted to determine if there is an active infection. Participants with active infection will be excluded from the study.; b) Participants who test positive for hepatitis C virus antibody will be required to have a negative result for hepatitis C viral ribonucleic acid (RNA) PCR before enrollment. Individuals with positive results for hepatitis C PCR will be excluded from the study.
* Chronic liver disease (Child-Pugh class C hepatic impairment), or history of liver or kidney transplants.
* Injury, trauma, and/or major surgery (mediastinoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery), major dental procedures (extractions, etc.) within 4 weeks of the first dose of SR604 or planned surgery during the study.
* Active infection requiring systemic antibiotic or antiviral therapy or in a sepsis condition within 14 days prior to the first dose of SR604.
* Any medical condition (eg, diabetes, obesity) which, in the Investigator's opinion, could compromise participant safety, interfere with SR604 metabolism, or put the study outcome at undue risk.

Primary outcomes:
measure: Parts A and B: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: Part A: From Baseline (Day 1) up to Day 57; Part B: From Baseline (Day 1) up to 3 months
measure: Parts A and B: Number of Participants with Clinical Abnormal Changes in Coagulations Markers
timeFrame: Part A: From Baseline (Day 1) till Day 57; Part B: From Baseline (Day 1) till Day 90
Secondary outcomes:
measure: Part A: Area Under the Serum Concentration-time Curve from time Zero to the Last Quantifiable Time Point (AUC[0-t])
timeFrame: From Baseline (Day 1) up to Day 57
measure: Part A: Area Under the Serum Concentration-time Curve from time Zero Extrapolated to Infinity (AUC[0-inf])
timeFrame: From Baseline (Day 1) up to Day 57
measure: Parts A and B: Maximum Concentration (Cmax) of SR604
timeFrame: Part A: From Baseline (Day 1) up to Day 57; Part B: From Baseline (Day 1) up to Day 90
measure: Parts A and B: Time to Maximum Concentration (tmax) of SR604
timeFrame: Part A: From Baseline (Day 1) up to Day 57; Part B: From Baseline (Day 1) up to Day 90
measure: Parts A and B: Terminal Half-life (T1/2) of SR604
timeFrame: Part A: From Baseline (Day 1) up to Day 57; Part B: From Baseline (Day 1) up to Day 90
measure: Part A: Clearance Following Extravascular Administration (CL/F) of SR604
timeFrame: From Baseline (Day 1) up to Day 57
measure: Part A: Volume of Distribution in Terminal Phase Following Extravascular Administration (Vz/F) of SR604
timeFrame: From Baseline (Day 1) up to Day 57
measure: Parts B: Concentration before the next dose administration (Ctrough)
timeFrame: From Baseline (Day 1) up to Day 90
measure: Parts B: Accumulation Ratio (R) of SR604
timeFrame: From Baseline (Day 1) up to Day 90
measure: Parts B: Number of Bleeding Events
timeFrame: From Baseline (Day 1) up to 3 months
measure: Parts B: Annualized Bleeding Rate (ABR) in Body and Targeted Joints
timeFrame: From Baseline (Day 1) up to 3 months
measure: Parts A and B: Number of Participants with Positive Antidrug Antibodies (ADAs)
timeFrame: Part A: From Baseline (Day 1) till Day 57; Part B: From Baseline (Day 1) till Day 90
Other outcomes:
Locations:
city: Glendale
country: United States
facility: California Clinical Trials Medical Group (CCTMG)
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Metairie
country: United States
facility: LA Center for Bleeding and Clotting Disorders - Metairie
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan Hospitals - Michigan Medicine
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Greenville
country: United States
facility: Brody School of Medicine at East Carolina University
state: North Carolina
city: Philadelphia
country: United States
facility: Perelman Center for Advanced Medicine (PCAM)- Penn Blood Disorders Program
state: Pennsylvania
Study officials:
References: