Introduction: Initiating bleeding prophylaxis early in life can prevent long-term joint damage and reduce the risk of intracranial hemorrhage (ICH) in infants with severe hemophilia A (HA); however, due to poor venous access and the risks and challenges associated with central venous access devices, many do not start prophylaxis until ≥1 year of age. In addition, early and intensive factor (F)VIII exposure increases inhibitor development risk. Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that replaces the function of activated FVIII, improving hemostasis. Early initiation of emicizumab may mitigate risks of spontaneous/traumatic bleeding in infants, including ICH, and inhibitor development. HAVEN 7 (NCT04431726) evaluated the safety, efficacy, pharmacokinetics and pharmacodynamics of emicizumab in infants aged 0-≤12 months with severe HA without inhibitors. Over 52 weeks, emicizumab maintained effective bleed control and was well tolerated. We present the results of an exploratory analysis of bleeding patterns during HAVEN 7.

Methods: HAVEN 7 is a Phase IIIb, multicenter, open-label study, details of which have been published previously (Pipe et al. Blood 2024). Participants had no history of, or minimal exposure (≤5 days) to, HA-related treatments and no prior emicizumab use or evidence of ICH. Participants received emicizumab 3 mg/kg weekly for 4 weeks, then every 2 weeks for 52 weeks. Annualized bleeding rates (ABRs) with 95% confidence intervals (CIs) were estimated using a negative binomial regression model and excluded surgical bleeds. The 72-hour rule was applied to ABRs (Donadel-Claeyssens et al. Haemophilia 2006). Bleeding patterns relative to age and the type and location of bleeds were explored; all bleeds were counted separately (no 72-hour rule).

Results: In total, 55 male infants were enrolled and had completed 52 weeks of emicizumab treatment at primary analysis clinical cutoff (May 22, 2023). Median (range) treatment duration was 100.3 (52-118) weeks. At informed consent, median (range) age was 4.0 (9 days-11 months) months. Thirty (54.5%) infants were minimally treated, with ≤5 FVIII exposure days (EDs) before enrollment (median [range] FVIII EDs: 2.0 [1.0-6.0]); 25 (45.5%) were previously untreated. Prior to emicizumab initiation, 36 (65.5%) infants had experienced 77 bleeds (median [range] age at time of first bleed: 1.0 [0-49] week[s]); 25 (32.5%) were spontaneous and 19 (24.7%) were traumatic.

Overall, 207 bleeds occurred in 46 (83.6%) emicizumab-treated infants; 18 (8.7%) were untreated spontaneous bleeds, 182 (87.9%) were untreated or treated traumatic bleeds, and 7 (3.4%) were surgery related. All 46 infants experienced traumatic bleeds (treated or untreated) and 7/46 (15.2%) infants also had untreated spontaneous bleeds. Model-based ABRs (95% CI) for treated bleeds and all bleeds were 0.40 (0.30-0.63) and 2.0 (1.49-2.66), respectively.

Three (1.5%) of the 200 non-surgical bleeds reported occurred in participants aged 0-<6 months at time of bleed; 6 (3.0%), 27 (13.5%), and 164 (82.0%), occurred in those aged 6-<9, 9-<12, and ≥12 months, respectively. A total of 25/46 (54.3%) participants reported 44 treated bleeds (all traumatic); 0 (0%) occurred in participants aged 0-<6 months at time of bleed, and 4 (9.1%), 10 (22.7%), and 30 (68.2%) in those aged 6-<9, 9-<12, and ≥12 months, respectively. The median (range) numbers of FVIII EDs per participant and FVIII infusions per bleed during emicizumab treatment were 0.0 (0.0-4.0) and 1.0 (1.0-3.0), respectively. Most non-surgical bleeds occurred on the head (156/200 [78.0%]); 60 (38.5%) of these were mouth bleeds (14 treated) and 38 (24.4%) were nose bleeds (all untreated). No ICH occurred. Three (1.5%), 11 (5.5%), and 29 (14.5%) bleeds occurred in the torso and upper and lower extremities, respectively. Four (2.0%) joint and five (2.5%) muscle bleeds occurred. Two infants aged 6-≤12 months at informed consent reported 28 (14.0%) traumatic and 21 (10.5%) spontaneous untreated bleeds, contributing to 24.5% of bleeds overall; most occurred on the head (24 and 14 bleeds, respectively).

Conclusions: This analysis is consistent with the results of previous pediatric studies, indicating that emicizumab is effective at maintaining low ABR in infants (0-≤12 months). All treated bleeds were traumatic and increased with age as infants gained mobility; no ICH occurred.

Disclosures

Carpenter:Genentech, Inc., Kedrion, Novo Nordisk: Honoraria. Rosenfelt:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Tzeng:Genentech, Inc.: Current Employment, Current holder of stock options in a privately-held company. Lim:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd.: Current equity holder in publicly-traded company. Pipe:Scientific Advisory Board GeneVentiv, Equilibra Bioscience: Membership on an entity's Board of Directors or advisory committees; Siemens, YewSavin: Research Funding; Apcintex, ASC Therapeutics, Bayer, Be Bio, BioMarin, CSL Behring, HEMA Biologics, Freeline, LFB, Metagenomi, Novo Nordisk, Pfizer, Poseida Therapeutics, Precision Bioscience, Regeneron, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, UniQure: Consultancy.

This content is only available as a PDF.
2024
Sign in via your Institution