Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial

Key Points • Subcutaneous emicizumab administered from birth has the potential to reduce the risk of ICH and joint bleeds before damage occurs.• Primary analysis of the HAVEN 7 trial indicates emicizumab is efficacious and well tolerated in infants with severe HA.


Full inclusion criteria
• Eligible participants were infants from birth to ≤12 months of age weighing ≥3 kg at the time of informed consent.
o Written informed consent was obtained from a parent or caregiver prior to any trial-specific assessments or procedures being performed.
o Participants had a diagnosis of severe congenital hemophilia A (HA) (intrinsic factor [F]VIII level ≤1%), a negative test for FVIII inhibitors (<0.6 Bethesda Unit [BU]/mL) locally assessed during the 2-week screening period, and no history of documented FVIII inhibitors, FVIII drug-elimination half-life <6 hours, or FVIII recovery <66%.
o Participants were previously untreated or minimally treated (i.e., up to 5 days of exposure with hemophilia-related treatments containing FVIII such as plasma-derived FVIII, recombinant FVIII, fresh frozen plasma, cryoprecipitate, or whole blood products).

Full exclusion criteria
• Infants who met any of the following criteria were excluded from trial entry: inherited or acquired bleeding disorder other than severe HA; use of systemic immunomodulators at enrollment or planned use during the trial; prior use of emicizumab prophylaxis; or receipt of an investigational drug to treat or reduce the risk of hemophilic bleeds within five drug-elimination half-lives of last drug administration, a non-hemophilia-related investigational drug within the last 30 days or five drug-elimination half-lives, whichever is shorter, or a concurrent investigational drug.
• Exclusion criteria also included current active severe bleeds (such as ICH; participants from birth to <3 months of age must not demonstrate evidence of active ICH at cranial ultrasound performed at screening); planned surgery during the trial (excluding minor procedures such as circumcision or central venous access device placement); a history of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection; being at high risk for thrombotic microangiopathies (TMA) in the investigator's judgement; previous or current treatment for thromboembolic disease (except previous catheterassociated thrombosis in infants for whom anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease; any hereditary or acquired maternal condition that may predispose the infant to thrombotic events; other diseases that may increase risk of bleeding or thrombosis; known infection with human immunodeficiency virus (HIV), hepatitis B virus or hepatitis C virus; serious infection requiring antibiotics or antiviral treatments within 14 days prior to screening; and any concurrent disease, treatment, abnormality in clinical laboratory tests, vital sign measurements, or physical examination findings that could interfere with the trial or that would, in the opinion of the investigator or Sponsor, preclude the infant's safe participation in and completion of the trial or interpretation of the trial results.
• Parents and caregivers had to be willing to allow receipt of blood or blood products, or any standard-of-care treatment for a life-threatening condition.
• Any other medical, social or other condition that may prevent adequate compliance with the trial protocol in the opinion of the investigator would also result in exclusion.

Definitions of bleed endpoints
Bleed endpoints assessed in the HAVEN 7 trial include treated bleed rate, all bleed rate, treated spontaneous bleed rate, and treated joint bleed rate.Bleeds by cause, type and location were recorded as an exploratory bleed-related endpoint.
For the purpose of the efficacy analyses, a standardized definition of bleed, adapted from criteria defined by the Subcommittee on Standards and Criteria, FVIII/X subcommittee of the International Society of Thrombosis and Hemostasis, [3] was used in this trial as follows: • An event was considered a treated bleed if coagulation factors were administered to treat signs or symptoms of bleeding (e.g., pain, swelling).An additional definition of all reported bleeds (irrespective of treatment with coagulation factors) was applied for a separate analysis.
• A new bleed was defined as a bleed occurring >72 hours after the last treatment for the original bleed.Any symptoms of bleeding that occurred ≤72 hours after the last treatment in the same location were considered the same bleed.
• Any injection administered to treat the bleed >72 hours after the preceding injection, was considered the first injection to treat a new bleed at the same location.
• Any bleed at a different location was considered a separate bleed regardless of time from the last injection.

Definitions of bleed causes
The assessment of a bleed was separated into spontaneous bleeds, traumatic bleeds, and bleeds related to procedure/surgery.Both spontaneous bleeds (i.e., the occurrence of hemorrhage for which the parents/caregivers cannot identify a reason) and traumatic bleeds (i.e., hemorrhage occurring secondary to an event such as trauma, "strenuous" activity, or "overuse") were recorded.
• Spontaneous bleeds: Bleeds were classified as spontaneous if the parents/caregivers recorded a bleed when there was no known contributing factor such as definite trauma, antecedent "strenuous" activity, or "overuse."The determination of what constitutes "strenuous" or "overuse" was at the discretion of the parents/caregivers.
• Traumatic bleeds: Bleeds were classified as traumatic if parents/caregivers recorded a bleed when there was a known or believed reason for the bleed.
• Bleeds related to procedure/surgery: for example, hematomas resulting from any surgery or invasive procedure (e.g., tooth extractions, venipuncture, or subcutaneous study drug administrations), or invasive diagnostic procedures (e.g., lumbar puncture, arterial blood gas determination, or endoscopy with biopsy) were considered a bleed related to procedure/surgery.Such bleeds were not associated with any trauma except the procedure/surgery in question.

Definition of bleed types
Bleed types were defined as follows: • Target joints: defined as a major joint (e.g., hip, elbow, wrist, shoulder, knee, or ankle) into which repeated bleeds occur (frequency of ≥3 bleeds into the same joint over a 24-week period) • Joint bleeds: defined as bleeds with bleed type 'joint bleed' reported on the Bleed and Medication Questionnaire (eBMQ) with at least one of the following symptoms: • Other (sites per the eBMQ)

Participant discontinuation from the trial
Reasons for participant discontinuation from the trial might include but are not limited to: withdrawal of consent by parent or caregiver, trial termination or site closure, adverse event, unacceptable toxicity with study treatment, participant's requirement for immune tolerance induction therapy, loss to follow-up, or participant non-compliance (defined as failure to comply with protocol requirements as determined by the investigator or Sponsor).

Blood collection
EDTA and citrate plasma were collected as previously described, [34]

oo
Receipt of vitamin K prophylaxis was mandatory if required by local standard practice.Participants required documentation of the details of bleeding episodes and hemophilia-related treatments since birth, and had no evidence of active intracranial hemorrhage (ICH), as confirmed by a negative cranial ultrasound at screening.o Participants had adequate hematologic function (defined as platelet count ≥100,000/µL [≥100 × 10 9 cells/L] and hemoglobin ≥8 g/dL [4.97 mmol/L]), and adequate hepatic function (defined as total bilirubin ≤1.5 × the age-specific upper limit of normal [ULN]; excluding infants with Gilbert syndrome or benign neonatal hyperbilirubinemia because of breastfeeding; and both aspartate aminotransferase and alanine aminotransferase ≤3 × the age-specific ULN) at screening, and adequate renal function (defined as serum creatinine ≤1.5 × the age-specific ULN; if the serum creatinine was ≥1.5 × the age-specific ULN, creatinine clearance by Schwartz estimation was required to be >70 mL/min/1.73m 2 ).

o
Increasing swelling or warmth of the skin over the joint o Increasing pain o Progressive loss of range of motion or difficulty in using the limb compared with baseline • Muscle bleeds (sites per the eBMQ)

Figure S2 .
Figure S2.Mean and individual FIX concentration at visit (A) over time and (B) by age at visit during the maintenance period

Figure S3 .
Figure S3.Mean and individual FX concentration (A) over time and (B) by age at visit during the maintenance period

Figure S4 .
Figure S4.Mean and individual aPTT (A) over time and (B) by age at visit during the maintenance period

Figure S5 .
Figure S5.Mean and individual TG peak height (A) over time and (B) by age at visit during the maintenance period

Figure S6 .
Figure S6.Mean and individual FVIII-like activity (A) over time and (B) by age at visit during the maintenance period