FVIII Exposure Analysis from the HAVEN 7 Study of Emicizumab in Infants with Severe Hemophilia A

Background: HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants (aged ≤12 months) with hemophilia A (HA). Subcutaneous emicizumab enables prophylaxis from birth, potentially reducing risk of bleeding and delaying factor (F)VIII inhibitor development associated with FVIII administration in infants. Primary analysis showed that emicizumab was efficacious and well tolerated in infants with severe HA without FVIII inhibitors at study entry (Pipe, Blood. 2024). During the study, 28/55 participants (50.9%) received FVIII. Two (3.6%) previously untreated participants (PUPs) tested positive for FVIII inhibitors; one on day 603 and one on day 428 post-enrollment, following FVIII exposure for bleed treatment, as well as surgeries in the second participant. This analysis gives further information on the total FVIII exposure days (EDs) pre- and on-study, providing additional context on the incidence of inhibitor development at primary analysis of HAVEN 7.

Methods: Participants were infants with severe HA with no history of FVIII inhibitors. At study entry, eligible infants could be PUPs or minimally treated participants (MTPs; defined as having 1–5 EDs with treatment containing FVIII). Inhibitors were measured by chromogenic Bethesda assay, and assessed in MTPs at baseline, and in any infant during the study after any 3 FVIII EDs or a block of FVIII EDs (≥2 consecutive doses). This analysis groups infants within the following FVIII ED ranges: 0, 1–3, 4–6, 7–9, and 10–13 EDs, considering both pre- and on-study periods to provide the total FVIII EDs since birth, in addition to demographic and F8 genotype information.

Results: At data cut-off (May 22, 2023), 55 male infants had received emicizumab for ≥52 weeks (median treatment duration: 100.3 weeks [range 52–118]). Pre-study, 30 (54.5%) infants had ≥1 FVIII ED (median: 1 day [range: 0–6]). The median number of on-study FVIII EDs was 1 (range 0–10).

At primary analysis, 44 (80.0%) infants had ≥1 FVIII ED since birth: 27 (49.1%) had 1–3 EDs, 12 (21.8%) had 4–6 EDs, 3 (5.5%) had 7–9 EDs, and 2 (3.6%) had 10–13 EDs. The median total FVIII EDs was 2 (range: 0–13). Family history of inhibitors was reported for 7 (12.7%) infants.

Eleven (20%) infants had no FVIII EDs at data cut-off, with a median age at time of informed consent of 2 (range: 0–10) months. At baseline, one of these infants had an intron 22 inversion, six were recorded as having ‘other’ F8 genotype (i.e. not a null mutation or missense mutation), and four had unknown genotype.

In the 1–3 FVIII EDs subgroup, median age at informed consent was 6 (range: 0–11) months. Nine infants had intron 22 inversion, one had a missense mutation, nine ‘other’ F8 genotype (two of whom also had intron 22 inversion), and 10 had unknown F8 genotype. One infant in this subgroup, with large F8 deletion and no history of FVIII inhibitors, developed an inhibitor after 3 nonconsecutive FVIII EDs for the treatment of two traumatic mouth bleeds.

In the 4–6 FVIII EDs subgroup, median age at informed consent was 7.5 (range: 0–11) months. One infant had a frameshift mutation, one had a missense mutation, two had ‘other’ F8 genotype, and eight had unknown F8 genotype.

In the 7–9 FVIII EDs subgroup, median age at informed consent was 9 (range: 2–11) months. One infant had a missense mutation; the remaining two had unknown F8 genotype.

In the 10–13 FVIII EDs subgroup, median age at informed consent was 2 (range: 1–3) months. One infant had intron 22 inversion, while the second had unknown F8 genotype. The infant with intron 22 inversion, who had a family history of inhibitors, developed FVIII inhibitors after 10 nonconsecutive FVIII EDs for a traumatic mouth bleed and surgical procedures (adenoidectomy and tonsillectomy).

Conclusions: In HAVEN 7, although 44/55 (80%) infants receiving emicizumab had ≥1 FVIII ED since birth, over two thirds of participants (69%) had ≤3 EDs. Two (3.6%) participants developed FVIII inhibitors, after 3 and 10 nonconsecutive EDs, respectively. As most people with HA develop FVIII inhibitors after a median of 14.5 EDs (Gouw, Blood. 2013), it will take more time to determine the inhibitor rate in people who start emicizumab alone as infants. Participants are continuing emicizumab prophylaxis during long-term follow-up in HAVEN 7; future analyses will provide further data on rate, timing of, and risk factors for, FVIII inhibitor development in this infant population receiving emicizumab prophylaxis.