Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B

Study APVO101-903 is a Phase 3/4, single arm, open-label clinical trial. The purpose of the study is to evaluate pharmacokinetics (PK), safety, and efficacy of APVO101 prophylaxis in severe or moderately severe hemophilia B subjects < 12 years of age. The study is designed to gather information in two age groups of previously treated (with a minimum of 50 previous ED to factor IX replacement therapy) pediatric patients, specifically those < 6 years of age and 6 to <12 years of age.

Study APVO101-903 consists of three distinct phases:

* PK Phase - PK evaluation will consist of administration of a single 75 ± 5 IU/kg dose, followed by factor IX activity and safety assessments up to 50 hours post-infusion.
* Treatment Phase - subjects will receive APVO101 prophylaxis (starting prophylaxis dose to be determined based on APVO101 recovery; ideally within the recommended dose range: 35 - 75 IU/kg; twice weekly) for 50 ED (approximately 6 months).
* Continuation Phase - subjects may continue to receive APVO101 prophylaxis (recommended dose range: 35 - 75 IU/kg; twice weekly) for an additional ≥ 50 ED.

• APVO101 (Drug), also known as IB1001, Recombinant factor IX, IXINITY: Subjects will receive a single IV dose of APVO101 twice weekly or at a frequency of infusions as determined appropriate by the investigator for the particular study subject for a total of 50 ED. The starting prophylaxis dose will be based on APVO101 recovery from PK Phase assessments (only pre-infusion and 15-30 minute post-infusion samples).

Primary outcomes

• Annualized Bleeding Rate (ABR) [Exposure Day 1 up to 50 exposure days (approximately 6 months)]: The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year.
• Annualized Bleeding Rate (ABR) Overall [Exposure Day 1 through study completion (up to 2.5 years)]: The primary efficacy variable was the ABR while on prophylaxis to prevent bleeding episodes. The ABR was defined as the number of bleeding episodes per year.

Secondary outcomes

• Concentration (Cmax) [Pre-infusion to 50 hours post-infusion]: Maximum post-infusion plasma concentration of FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
• Area Under the Curve (0-inf) [Pre-infusion to 50 hours post-infusion]: Area under plasma concentration curve, FIX activity-time profile from time zero extrapolated to infinity. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
• Mean Residence Time (MRT) [Pre-infusion to 50 hours post-infusion]: MRT is the average time the molecules of drug reside in the body before elimination.
• Terminal Half-Life (t 1/2) [Pre-infusion to 50 hours post-infusion]: Terminal half-life is the length of time required for the concentration of drug to decrease by one half of its starting dose in the body. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
• Clearance (CL) [Pre-infusion to 50 hours post-infusion]: Clearance is a measure of the volume of plasma from which FIX activity is removed per unit time. Weight normalized clearance calculated as CL=Dose/AUC 0-inf. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
• Volume of Distribution at Steady-State (Vdss) [Pre-infusion to 50 hours post-infusion]: Volume of distribution is defined as the theoretical volume in which the total amount of FIX would need to be uniformly distributed to produce the observed plasma concentration of FIX. Steady state volume of distribution (Vdss) is the apparent volume of distribution at steady-state. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
• Incremental Recovery (IR) [Pre-infusion to 50 hours post-infusion]: Incremental recovery was the increase in circulating FIX activity for every international unit (IU) of APVO101 administered per kilogram of body weight of participant. FIX activity was measured at the following time points post infusion: 15-30 minutes, 4-6 hours, 24-26 hours and 46-50 hours.
• Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) [Exposure Day 1 up to 50 exposure days (approximately 6 months)]: Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution; 4. Poor: no improvement or condition worsens.
• Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) [Exposure Day 1 through study completion (up to 2.5 years)]: Subjects rated APVO101 efficacy for each bleeding episode based on a four-point scale: 1. Excellent: a dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size 2. Good: pain relief or reduction in hemorrhage site size that may have required an additional infusion for resolution; 3. Fair: probable or slight beneficial response usually requiring one of more additional infusions for resolution; 4. Poor: no improvement or condition worsens.
• Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase) [Exposure Day 1 up to 50 exposure days (approximately 6 months)]: The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'.
• Investigator Rating of APVO101 Prophylaxis Efficacy (Overall) [Exposure Day 1 through study completion (up to 2.5 years)]: The investigator will indicate the overall assessment of APVO101 prophylaxis efficacy, considering the absence of bleeding episodes, site, severity and types of bleeding episodes treated, and other factors that might influence the therapeutic response. The investigator's efficacy assessment categories for prophylaxis will include: 'effective', 'partially effective' and 'not effective'.
• Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase) [Exposure Day 1 up to 50 exposure days (approximately 6 months)]: Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'.
• Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall) [Exposure Day 1 through study completion (up to 2.5 years)]: Of the bleeding episodes requiring treatment, the investigator considered the site, severity and type of the bleeding episode while evaluating efficacy for control and management of the bleeding episode. The investigator's efficacy assessment categories control of bleeding episodes included: 'effective', 'partially effective' and 'not effective'.

Other outcomes

• Spontaneous Annualized Bleeding Rate (Treatment Phase) [Exposure Day 1 up to 50 exposure days (approximately 6 months)]: Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause).
• Spontaneous Annualized Bleeding Rate (Overall) [Exposure Day 1 through study completion (up to 2.5 years)]: Includes annualized bleeding rate for spontaneous bleeding (i.e. bleeds that occur without obvious cause).
• Occurrence of Inhibitory Factor IX Antibodies (Overall) [Exposure Day 1 through study completion (up to 2.5 years)]: Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\])
• Occurrence of Non-Inhibitory Factor IX Antibodies (Overall) [Exposure Day 1 through study completion (up to 2.5 years)]: Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\])
• Occurrence of Anti-CHOP Antibodies (Overall) [Exposure Day 1 through study completion (up to 2.5 years)]: Incidence of APVO101 immunogenicity response (development of inhibitory, non-inhibitory factor IX binding antibodies and incidence of antibodies to Chinese hamster ovary cell proteins \[CHOP\])
• Thrombogenicity Assessment - D-Dimer [Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion]: This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.
• Thrombogenicity Assessment - Thrombin/Antithrombin (TAT) Complex [Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion]: This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.
• Thrombogenicity Assessment - Prothrombin Fragment 1+2 [Day 1 (pre-dose), 15-30 minutes, 4-6 hours and 24-26 hours post-infusion]: This study included testing of thrombogenic markers at the PK stage to evaluate for thrombotic risk.

Sex: All, ages: any to 11 Years

Inclusion Criteria:

1. Age: < 11.5 years of age at the time of the first dose and < 12 years throughout the Treatment Phase of the study (for at least 50 ED).
2. Informed consent: subject's parent or legal guardian written Institutional Review Board (IRB)/Ethics Committee (EC)-approved informed consent. An assent form (IRB/EC-approved) will be obtained, when required by local regulations/guidelines.
3. Willingness and ability to make the required study visits, and follow instructions while enrolled in the study (for at least 50 ED; approximately 6 months).
4. Documented severe or moderately severe hemophilia B diagnosis (factor IX activity ≤ 2 IU/dL); in addition, severity may be indicated by the occurrence of one or more joint bleeding episode(s) at any point in the child's medical history requiring infusion(s) to replace factor IX.
5. Subjects must be on prophylaxis or switch to a prophylaxis regimen for the duration of the study.
6. Previously treated patients with a minimum of 50 ED (as documented and determined by the investigator) to a preparation/blood components containing factor IX.
7. Willingness to adhere to the 4-day washout period of any factor IX replacement therapy prior to PK evaluation. In case of previous exposure to a factor IX product with a prolonged half-life, a washout period of 3 half-lives is required in order to achieve steady state factor IX level prior to exposure to APVO101.
8. Immunocompetent (CD4 count > 400/mm3) and not receiving immune modulating or chemotherapeutic agents.
9. Platelet count at least 150,000/mm3.
10. Liver function: alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2 times the upper limit of the normal range.
11. Total bilirubin ≤ 1.5 times the upper limit of the normal range.
12. Renal function: serum creatinine ≤ 1.25 times the upper limit of the normal range.
13. Hemoglobin ≥ 7 g/dL.

Exclusion Criteria:

1. History of factor IX inhibitor ≥ 0.6 Bethesda Units (BU); confirmed by the screening result.
2. Existence of another coagulation disorder.
3. Evidence of thrombotic disease, fibrinolysis, or disseminated intravascular coagulation (DIC).
4. Use of an investigational drug within 30 days prior to study entry.
5. Previous use of APVO101.
6. Use of medications that could impact hemostasis, such as aspirin.
7. Known hypersensitivity to the active substance or to any of the excipients in the investigational products.
8. Known allergic reaction to hamster proteins.
9. History of poor compliance, geographic isolation, unreliable transportation, a serious medical or social condition, or any other circumstance that, in the opinion of the investigator, would interfere with participation or compliance with the study protocol.
10. History of adverse reaction to either plasma-derived factor IX or recombinant factor IX that interfered with the subject's ability to treat bleeding episodes with a factor IX product.
11. History of any medical condition that would impact the efficacy evaluation and/or safety evaluation of the study product.

Participant flow

Outcome results

• Annualized Bleeding Rate (ABR) (Primary), Mean, bleeding episodes per year: APVO101 - Safety Population 2.93 +/- 4.59
• Annualized Bleeding Rate (ABR) Overall (Primary), Mean, bleeding episodes per year: APVO101 - Safety Population 2.34 +/- 4.23
• Concentration (Cmax) (Secondary), Mean, IU/dL: APVO101 - Safety Population 60.1 +/- 12.2
• Area Under the Curve (0-inf) (Secondary), Mean, IU/dL/hr: APVO101 Prophylaxis - Safety Population 1170 +/- 231
• Mean Residence Time (MRT) (Secondary), Mean, hours: APVO101 Prophylaxis - Safety Population 20 +/- 2.53
• Terminal Half-Life (t 1/2) (Secondary), Mean, hours: APVO101 Prophylaxis - Safety Population 16.3 +/- 2.2
• Clearance (CL) (Secondary), Mean, mL/(kg*hr): APVO101 Prophylaxis - Safety Population 6.8 +/- 1.5
• Volume of Distribution at Steady-State (Vdss) (Secondary), Mean, mL/kg: APVO101 Prophylaxis - Safety Population 134 +/- 30.6
• Incremental Recovery (IR) (Secondary), Mean, IU/dL per IU/kg: APVO101 Prophylaxis - Safety Population 0.790 +/- 0.156
• Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Treatment Phase) (Secondary), Count of units, bleeding episodes: APVO101 Prophylaxis - Safety Population 10
• Subject Rating of APVO101 Efficacy - Evaluated at the Bleeding Episode Level (Overall) (Secondary), Count of units, bleeding episodes: APVO101 Prophylaxis - Safety Population 28
• Investigator Rating of APVO101 Prophylaxis Efficacy (Treatment Phase) (Secondary), Count of units, prophylactic efficacy assessment: APVO101 Prophylaxis - Safety Population 80
• Investigator Rating of APVO101 Prophylaxis Efficacy (Overall) (Secondary), Count of units, prophylactic efficacy assessment: APVO101 Prophylaxis - Safety Population 167
• Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Treatment Phase) (Secondary), Count of units, efficacy for control of bleeding episode: APVO101 Prophylaxis - Safety Population 16
• Investigator Rating of APVO101 Efficacy for Control and Management of Bleeding Episodes (Overall) (Secondary), Count of units, efficacy for control of bleeding episode: APVO101 Prophylaxis - Safety Population 35
• Spontaneous Annualized Bleeding Rate (Treatment Phase) (Other pre specified), Mean, spontaneous bleeding episodes: APVO101 Prophylaxis - Safety Population 0.81 +/- 1.93
• Spontaneous Annualized Bleeding Rate (Overall) (Other pre specified), Mean, spontaneous bleeding episodes: APVO101 Prophylaxis - Safety Population 0.63 +/- 1.26
• Occurrence of Inhibitory Factor IX Antibodies (Overall) (Other pre specified), Count of participants, Participants: APVO101 - Safety Population 0
• Occurrence of Non-Inhibitory Factor IX Antibodies (Overall) (Other pre specified), Count of participants, Participants: APVO101 - Safety Population 3
• Occurrence of Anti-CHOP Antibodies (Overall) (Other pre specified), Count of participants, Participants: APVO101 - Safety Population 3
• 3 more outcome measures not shown.

Adverse events

Time frame: Adverse events were monitored after the first dose of APVO101 through study completion (up to 2.5 years) with a minimum follow-up period of 30 days.

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2020-07-29)
• Statistical Analysis Plan (PDF, 2023-03-28)

• Khaled Mohamed, Study chair, Medexus Pharma, Inc.