Safety and Pharmacokinetics of Subcutaneous Injection of OCTA101 in Adult Patients With Severe Hemophilia A

Study Overview
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Brief Summary
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This Phase 1/2 study will be a dose escalation study in adults in 5 cohorts (named cohorts 1, 2, 3, 5 and 6), with the main purpose to assess the safety of subcutaneous injection of OCTA101 (a human-cl rhFVIII and recombinant human von Willebrand Factor fragment dimer) in previously treated adult patients with severe hemophilia A. The study also aims to assess the pharmacokinetics (PK) characteristics, dose proportionality, and subcutaneous bioavailability of OCTA101 compared with intravenous administration of Nuwiq (Human-cl rh FVIII), in order to define the prophylactic treatment (dose and injection interval) that would result in protective trough levels of FVIII:C for future Phase 3 studies. Cohorts 1, 2, 3 and 5 will undergo a single injection of OCTA101, with cohorts 1, 2 and 3 proceeding to 3-month daily dosing prophylactic treatment for 3 months by Data Monitoring Committee recommendation. Cohorts 1 and 2 will undergo a further PK at the end of the daily injection period. A further cohort, cohort 6, will have an initial 4 to 6-week run-in treatment period with Nuwiq intravenous prophylaxis followed by 12.5 IU/kg OCTA101 subcutaneous daily prophylaxis for >3 up to 6-7 months.

Official Title
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Phase 1/2 Study to Assess the Safety and Pharmacokinetics of Subcutaneous Injection of OCTA101 in Previously Treated Adult Patients With Severe Hemophilia A

Conditions
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Severe Hemophilia A

Intervention / Treatment
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* Drug: OCTA101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe hemophilia A (<1% FVIII:C) as documented in medical records Males ≥18 years of age Subjects who have had ≥150 exposure days (EDs) with a FVIII product Written informed consent for study participation obtained before undergoing any study specific procedures Exclusion Criteria: Previous participation in this trial Use of an Investigational Medicinal Product within 30 days prior to the first OCTA101 injection History of FVIII inhibitors titre ≥0.6 BU/mL defined by medical records Inhibitors to FVIII (≥0.6 BU/mL) at screening measured by Nijmegen modified Bethesda method at central laboratory Human immunodeficiency virus (HIV) positive subjects with a CD4+ count <200/mL Clinically significant anemia at screening (hemoglobin <8 g/dL) Presence of any significant comorbidity (at the discretion of the investigator) that might confound the interpretation of the study data and/or that might put the patient at undue risk by participating in the trial Any coagulation disorder other than hemophilia A AST or ALT levels >3 times the upper limit of normal Creatinine >120 μmol/L Platelet count <100,000 μL BMI ≥30 kg/m² For Cohort 6, patients with a positive LumiTope test at screening will be excluded

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>50 IU/kg (n=4): single-period investigation with a single sc dose of 50 IU/kg OCTA101 profiled up to 72 hours after dosing in adult male patients with severe hemophilia A. Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 2, alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. | Drug: OCTA101<br>* OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).<br>|
| Experimental: Cohort 2<br>100 IU/kg (n=4): single-period investigation with a single sc dose of 100 IU/kg OCTA101 profiled up to 96 hours after dosing in adult male patients with severe hemophilia A. Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 3, alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. | Drug: OCTA101<br>* OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).<br>|
| Experimental: Cohort 3<br>50 IU/kg (n=8): two-period investigation of a single iv dose of 50 IU/kg Human-cl rhFVIII (Nuwiq) profiled for up to 72 hours after dosing followed by sc dose of 50 IU/kg OCTA101 profiled up to 72 hours in adult male patients with severe hemophilia A. Treatments will be administered in fixed sequence, with Human-cl rhFVIII first. Following review of safety and tolerability data by Data Monitoring Committee, proceed with Cohort 4 and 5 alongside daily prophylactic dosing (40-60 IU/kg) for 3 months. | Drug: OCTA101<br>* OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).<br>|
| Experimental: Cohort 5<br>(n=4): Three-period investigation of single sc doses of 20, 40, and 60 IU/kg OCTA101 profiled up to 72 hours after dosing. Treatments were to be administered in fixed dose-ascending sequence. | Drug: OCTA101<br>* OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).<br>|
| Experimental: Cohort 6<br>(n≥16): Following an initial 4 to 6-week run-in period with Nuwiq iv prophylaxis, >3-6 months daily prophylactic treatment with 12.5 IU/kg OCTA101 sc, then 25 IU/kg OCTA101 sc for a further 6-7 months (exact dosing depends on available vial sizes). In case of two spontaneous bleeding episodes, after having completed at least 3 months with 12.5 IU/kg OCTA101 daily treatment the individual treatment dose will be increased from 12.5 to 25 IU/kg. Site of administration (abdomen or thigh) to be chosen by the patient. A further treatment phase with 40 IU/kg OCTA101 will be discussed with the DMC, once results of earlier dosing phases are available. | Drug: OCTA101<br>* OCTA101 is composed of OCTA8 (human-cl rhFVIII - Nuwiq Intermediate 2 Q-Eluate) and OCTA12 (recombinant human VWF fragment dimer).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | Approximately 4 months; up to 11 months for cohort 6 | 
| Dose-limiting toxicities (DLTs) |  | Approximately 4 months; up to 11 months for cohort 6 | 
| Thromboembolic events |  | Approximately 4 months; up to 11 months for cohort 6 | 
| Local injection site reactions |  | Approximately 4 months; up to 11 months for cohort 6 | 
| Inhibitor formation to FVIII |  | 5 days to approximately 4 months; up to 11 months for cohort 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Area under the concentration-time curve (AUC) of FVIII:C |  | Up to 120 hours after injection | 
| Efficacy: Maximum plasma concentration (Cmax) of FVIII:C |  | Up to 120 hours after injection | 
| Efficacy: Time for reaching maximum plasma concentration (Tmax) of FVIII:C |  | Up to 120 hours after injection | 
| Efficacy: In vivo recovery (IVR) of FVIII:C |  | Up to 120 hours after injection | 
| Efficacy: Half-life (t1/2) of FVIII:C |  | Up to 120 hours after injection | 
| Efficacy: Mean residence time (MRT) of FVIII:C |  | Up to 120 hours after injection | 
| Efficacy: Area under the concentration-time curve (AUC) of OCTA12 (a recombinant von Willebrand Factor fragment dimer) |  | Up to 120 hours after injection | 
| Efficacy: Maximum plasma concentration (Cmax) of OCTA12 (a recombinant von Willebrand Factor fragment dimer) |  | Up to 120 hours after injection | 
| Efficacy: Time for reaching maximum plasma concentration (Tmax) of OCTA12 (a recombinant von Willebrand Factor fragment dimer) |  | Up to 120 hours after injection | 
| Efficacy: In vivo recovery (IVR) of OCTA12 (a recombinant von Willebrand Factor fragment dimer) |  | Up to 120 hours after injection | 
| Efficacy: Half life (t1/2) of OCTA12 (a recombinant von Willebrand Factor fragment dimer) |  | Up to 120 hours after injection | 
| Efficacy: Mean residence time (MRT) of OCTA12 (a recombinant von Willebrand Factor fragment dimer) |  | Up to 120 hours after injection | 
| Efficacy: Total annualized bleeding rate | Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6 | 3 months; approximately 11 months for cohort 6 | 
| Efficacy: Spontaneous annualized bleeding rate | Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6 | 3 months; approximately 11 months for cohort 6 | 
| Efficacy: Total annualized treated bleeding rate | Total annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6 | 3 months; approximately 11 months for cohort 6 | 
| Efficacy: Spontaneous annualized treated bleeding rate | Spontaneous annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6 | 3 months; approximately 11 months for cohort 6 | 
| Efficacy: Traumatic annualized bleeding rate | Traumatic annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6 | 3 months; approximately 11 months for cohort 6 | 
| Efficacy: Joint annualized bleeding rate | Joint annualized bleeding rate during daily subcutaneous treatment with OCTA101 for cohorts 1, 2, 3 and 6 | 3 months; approximately 11 months for cohort 6 | 
| Efficacy: FVIII:C trough and peak plasma levels | FVIII:C trough and peak plasma levels during daily dosing for cohorts 1, 2, 3 and 6 | 3 months; approximately 11 months for cohort 6 | 
| Efficacy: Efficacy of treatment of bleeding episodes using Score (4-point) | Score (4-point) to assess the efficacy of treatment of bleeding episodes with Human-cl rhFVIII. Treatment efficacy will be assessed using predefined criteria to score either 'Excellent', 'Good', 'Moderate' or 'None'. All efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated'. | 5 days to approximately 11 months | 
| Safety: Antibody formation to OCTA12 |  | 5 days to approximately 11 months | 
| Safety: OCTA12 plasma levels | OCTA12 plasma levels during daily dosing (cohorts 1 to 3) | 3 months | 
| Safety: Change in hemoglobin | Hemoglobin compared to baseline | 5 days to approximately 11 months | 
| Safety: change in alanine aminotransferase (ALT) | Alanine aminotransferase (ALT) compared to baseline, measured in U/L | 5 days to approximately 11 months | 
| Safety: change in aspartate transaminase (AST) | Aspartate transaminase (AST) compared to baseline, measured in U/l | 5 days to approximately 11 months | 
| Safety: Vital signs | Vitals signs compared to baseline | 5 days to approximately 11 months | 
| Safety: Physical examination results | Physical examination results compared to baseline | 5 days to approximately 11 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophilia A, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Factor VIII