A treatment bridge for infants with hemophilia

In this issue of Blood, Pipe et al¹ report on the high safety and efficacy of emicizumab, a recombinant, humanized, bispecific monoclonal antibody, in children <1 year of age with severe hemophilia A (HA) (<1% factor VIII [FVIII]) and without FVIII antibodies (inhibitors). This novel, practice-changing, large-study finding, not reported previously in the infant age group, is described in this multicenter, phase 3b, open-label, single-arm study. Long-term data will be collected over the next 7 years.

HA is a rare bleeding disorder characterized by soft-tissue, mucosal, intracranial, and joint/muscle bleeding, which often presents at a very early age. Prevention of bleeding (prophylaxis) to minimize the morbidity of joint bleeding and the devastating effects of intracranial hemorrhage² is universally recommended to begin at an early age by administration of FVIII infusions 2 to 4 times/week, often requiring use of an indwelling venous catheter. Potential problems with catheter use include infections and thrombosis, and repetitive FVIII infusions may lead to inhibitors in approximately 30% of treated patients, appearing after a relatively small number of infusions (n = 9 to 36).³ 

Emicizumab acts as an immunoglobulin G molecular bridge between activated factors IX and X and as a substitute for the important role of FVIII.⁴ The drug is given subcutaneously, a major advantage for infants, thus avoiding potential issues with intravenous access. This monoclonal antibody has demonstrated a high degree of safety and efficacy among patients with HA over the past 6 to 7 years (HAVEN 1 to 6 clinical trials) encompassing a wide age spectrum, with and without inhibitors, in both minor and major surgeries,^4-7 and with various levels of HA disease severity (mild to severe; HAVEN 6). Recently, emicizumab prophylaxis has been recommended for the treatment of young children and infants with HA by both the World Federation of Hemophilia and the Medical and Scientific Advisory Council of the National Bleeding Disorders Foundation.^8,9 

There were 55 patients enrolled in the study. Median age was 4 months (45% enrolling in the first 3 months), with all infants consented to participate before 1 year of age. Forty-five percent of the patients had no bleeds before enrollment, whereas 55% were minimally treated (1 to 5 exposure days of hemophilia-related treatment containing FVIII). After the loading dose, all patients were treated with standard emicizumab dosing (3 mg/kg every 2 weeks) for 1 year, after which 9% were switched to an approved monthly dose. One patient also underwent upward dosing (3 mg/kg every week) at 1 year due to low emicizumab levels. The follow-up period was approximately 2 years from study entry until data cutoff, with 95% compliance with the emicizumab dosing regimen.

The vast majority of patients had at least 1 bleed (207 total bleeds among 46 of the 55 patients; 84%) and a comparably high percentage of these bleeds (88%) were trauma related. Interestingly, 48 of the 207 bleeds (23%) occurred in 2 patients who did not require FVIII treatment. The few spontaneous bleeds were mostly mucosal related (eg, epistaxis) and accounted for 9% of the total bleeds. In addition, 3% of the bleeds were procedure or surgery related. Twenty-five patients (25 of 55; 46%) required FVIII replacement for a bleed(s), all trauma related. There were no intracranial hemorrhages among the study population despite 4 patients experiencing head trauma. Joint bleeds were rare (5%), but they did occur and were also trauma related.

Although previous HAVEN studies, encompassing approximately 500 subjects, demonstrated relatively low numbers of antidrug antibodies (ADA; n = 3; all neutralizing antibodies with low drug levels), thrombotic microangiopathy (TMA; n = 3), and thromboembolism (TE; n = 2),⁷ there were no cases of ADA, TMA, or TE found in the 55 patients assessed by Pipe and colleagues. The TMA and TE cases in previous HAVEN studies were thought to be related to concomitant use of bypassing factor replacement therapy and, when these agents were not utilized, there were no biomarkers of increased thrombin.¹⁰ In the current trial, 2 patients developed a FVIII inhibitor between 1 and 2 years of the study and both were discovered after FVIII exposure. A small number of subjects (16%) had grade 1 injection-site reactions, which did not cause dose modification or study discontinuation. All serious adverse events were due to hospitalization and not thought to be related to emicizumab (see figure). One subject had an anaphylactic reaction due to an egg allergy, which was also not drug related.

Emicizumab simulates approximately 21 to 26 U/dL FVIII-like levels at steady state, thus converting patients with severe HA to mild HA.¹⁰ This may explain why some patients from HAVEN 7 still experienced bleeding (including joint bleeding), mostly with trauma, and why a few developed inhibitors after exposure to FVIII. Apart from these 2 pitfalls, longer term follow-up with this monoclonal antibody is needed to assess for ADA development; effect of injection-site reactions; use at <3 months, especially in neonates; joint damage; and potential safety signals. The HAVEN 7 study will continue to collect data to help address these issues.

This first clinical trial for infants with HA without inhibitors has demonstrated that emicizumab is safe, efficacious, and easily administered. This treatment almost eliminates the need for intravenous FVIII and its attendant side effects while effectively eliminating the potential disastrous outcomes of intracranial hemorrhage and joint damage. We have made enormous progress in HA treatment over the last 70+ years and the emicizumab bridge in infants adds to this success.

Conflict-of-interest disclosure: The author declares no competing financial interests.