Emicizumab prophylaxis in children with hemophilia A with factor VIII inhibitors in China (HAVEN 5)

To the Editor: Hemophilia A (HA) is a congenital bleeding disorder associated with spontaneous or traumatic bleeds, primarily affecting males.[1] HA is characterized by a deficiency or lack of coagulation factor VIII (FVIII), causing recurrent bleeding, predominantly into joints, muscles, and soft tissues.[1] In children with HA, especially infants, early bleed control is crucial to prevent potentially life-threatening bleeding and the development of joint arthropathy over time.[2] Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that bridges activated factor IX (FIX) and factor X (FX) to substitute for the function of deficient activated FVIII, thereby improving hemostasis in people with HA (PwHA). The long half-life of emicizumab allows for once-weekly (QW), every 2 weeks (Q2W), and every 4 weeks (Q4W) dosing regimens.[3] Emicizumab was approved in China in 2018 for adults and children with HA and inhibitory antibodies to FVIII (inhibitors), and in 2021 for adults and children with severe HA without inhibitors; however, data in the Chinese pediatric population with HA remain limited. The Phase 3 HAVEN 5 study (NCT03315455, https://clinicaltrials.gov/study/NCT03315455?term=NCT03315455%20&rank=1) was designed to assess the efficacy, safety, pharmacokinetics, pharmacodynamics, and immunogenicity of emicizumab in PwHA in the Asia–Pacific region.[4] The study was conducted in compliance with the Declaration of Helsinki, and all informed consent guidelines; the protocol was approved by the Institutional Review Boards/Independent Ethics Committees at each participating site and carried out in accordance with applicable regulations. Adult/adolescent participants (aged ≥12 years with severe HA without FVIII inhibitors, or HA of any severity with FVIII inhibitors) were randomized to one of three arms (arms A, B, or C),[4] comparing emicizumab prophylaxis with no prophylaxis. Pediatric participants (<12 years old) were enrolled into an additional arm, arm D, which was analyzed separately [Supplementary Figure 1, https://links.lww.com/CM9/C819]. Outcome data after at least 24 weeks of treatment in individuals from arms A–C have been previously reported.[4] Here, we report findings from arm D, investigating emicizumab in pediatric PwHA aged <12 years with FVIII inhibitors from China. Participants were enrolled from four sites in China [Supplementary file, https://links.lww.com/CM9/C819 for inclusion and exclusion criteria]. Emicizumab was given subcutaneously as a loading dose of 3 mg/kg QW for 4 weeks, followed by maintenance dosing of 1.5 mg/kg QW thereafter. The primary efficacy endpoint for arm D was the number of treated bleeds; treated joint bleeds, treated target joint bleeds, treated spontaneous bleeds, and all bleeds were also assessed. The safety of emicizumab was assessed via incidence of adverse events (AEs), including thromboembolic events (TEs) and thrombotic microangiopathies (TMAs), and development of anti-drug antibodies (ADAs). The pharmacokinetic objective was to characterize the mean trough plasma concentrations of emicizumab. Exploratory endpoints included pharmacodynamics (activated partial thromboplastin time [aPTT], and FVIII-like activity) and safety biomarkers (D-dimer and prothrombin time). Data collection and analyses are detailed in the Supplementary file, https://links.lww.com/CM9/C819. A total of 16 children with HA were screened for arm D, and 15 of them enrolled (one withdrew consent before enrollment). All 15 participants were included in this analysis (clinical cut-off date: August 3, 2022). The median (range) duration of emicizumab exposure was 64.1 (61.1–67.3) weeks. No participants had their dose up-titrated due to suboptimal bleed control. All participants were Chinese and male [Supplementary Table 1, https://links.lww.com/CM9/C819]. The median (range) age was 8 (3–11) years at enrollment. All participants had severe HA and documentation of high-titer (≥5 Bethesda units [BU]/mL) FVIII inhibitors at baseline. The model-based annualized bleed rate (ABR [95% confidence interval (CI)]) for treated bleeds was 0.6 (0.3–1.3), with values of 0.1 (0–0.4), 0.3 (0.1–0.9), and 2.8 (1.5–5.3) for treated joint bleeds, treated spontaneous bleeds, and all bleeds, respectively [Figure 1A; Supplementary Table 2, https://links.lww.com/CM9/C819]. The proportion (95% CI) of participants with zero bleeds during the study was 60.0% (32.3%–83.7%), 93.3% (68.1%–99.8%), 80.0% (51.9%–95.7%), and 26.7% (7.8%–55.1%) for treated bleeds, treated joint bleeds, treated spontaneous bleeds, and all bleeds, respectively [Figure 1B]. No treated target joint bleeds were reported during the study.Figure 1: Bleeding endpoints in children with hemophilia A with factor VIII inhibitors in China. *Model-based ABRs were derived using a negative binomial regression model. †Treated target joint bleeds were not estimable because none occurred during the study. ABR: Annualized bleed rate; CI: Confidence interval.The most common AE was upper respiratory tract infection, which was experienced by 40% (6/15) of participants. AEs that were considered related to emicizumab treatment by the investigators were reported in four participants [Supplementary Table 3, https://links.lww.com/CM9/C819]: two participants displayed increased levels of blood alkaline phosphatase (three events), one displayed abnormal hepatic function (three events), and another displayed sinus bradycardia (one event); all were grade 2 or below. No serious AEs, deaths, or AEs leading to treatment withdrawal were reported. No injection-site reactions, TEs, or TMAs were reported. No participant tested positive for ADAs. Mean trough concentrations of emicizumab increased with QW loading doses of 3 mg/kg to achieve a mean (standard deviation [SD]) concentration of 55.6 (7.6) µg/mL at week 5 [Supplementary Figure 2, https://links.lww.com/CM9/C819]. Mean trough concentrations of approximately 50 µg/mL were maintained thereafter with the emicizumab 1.5 mg/kg QW maintenance dose. A sustained pharmacodynamic effect was observed [Supplementary Figure 3, https://links.lww.com/CM9/C819]. Mean (SD) FVIII-like activity increased to 22.8 (2.1) U/dL at week 5 and generally remained stable around 20 U/dL during emicizumab treatment. In all but one participant, who had missing baseline data, aPTT was elevated at baseline (due to FVIII deficiency), decreased to values between 24.1 and 31.3 seconds at week 2 (Day 8; following the first dose of emicizumab), and generally remained within or below the reference range. D-dimer and prothrombin time were unaffected by treatment with emicizumab and remained stable throughout the study. Overall, results from this study demonstrated that emicizumab prophylaxis is well tolerated in Chinese children (<12 years) with severe HA and FVIII inhibitors. Data from arms A–C of HAVEN 5 showed that emicizumab significantly reduced ABRs in adolescent/adult PwHA (aged ≥12 years), and was well tolerated, with a favorable safety profile.[4] No TEs or TMAs were reported in any arms of HAVEN 5 at the time of the latest clinical cut-off date. In this analysis of the pediatric arm D population, emicizumab QW dosing was associated with substantial and clinically meaningful bleed control, similar to the pediatric HAVEN 2[5] and HOHOEMI studies.[6] The model-based ABR (95% CI) in arm D for treated bleeds was similar to that seen in participants in the HAVEN 2 trial who were treated with the same QW dosing regimen (0.3 [0.2–0.5]; n = 65).[5] For comparison, in those who received the Q2W and Q4W dosing regimens, model-based ABRs were 0.2 (0–1.7; n = 10) and 2.2 (0.7–6.8; n = 10), respectively,[5] while in the HOHOEMI study, ABRs (95% CIs) for treated bleeds were 1.3 (0.6–2.9) and 0.7 (0.2–2.6) in the Q2W and Q4W cohorts, respectively.[6] The model-based ABR (95% CI) for treated joint bleeds during the present study was 0.1 (0–0.4), with 93.3% (14/15) of participants experiencing no treated joint bleeds and 100% (15/15) experiencing no treated target joint bleeds. This is notable in a population where 40% (6/15) of participants had target joints at baseline. Comparable results were seen in HAVEN 2, where 38.6% (34/88) of the emicizumab-treated participants had target joints at baseline, with 84.6% (55/65) having no treated joint bleeds and 95.4% (62/65) having no treated target joint bleeds; the model-based ABR (95% CI) for treated joint bleeds was 0.2 (0–0.3). Other studies of different hemostatic agents in pediatric PwHA have reported lower proportions of participants with target joints, but with similar or slightly higher ABRs for joint bleeds during follow-up.[6–8] No participants in the present study tested positive for ADAs; this was also the case in the HOHOEMI study.[6] In HAVEN 2, 4.5% (4/88) of participants tested positive for ADAs: in two participants, the antibodies were neutralizing in vitro; one participant discontinued emicizumab due to loss of efficacy, while in the final participant, the ADAs disappeared over time without breakthrough bleeding or intervention.[5] Overall, the incidence of ADAs in emicizumab clinical trials has been reported to be low.[9] A sustained exposure of emicizumab was observed in arm D of HAVEN 5, with therapeutic emicizumab plasma levels achieved following the loading dose period, which was comparable to HAVEN 2 and HOHOEMI.[5,6] In all three pediatric studies, the mean steady-state trough concentrations of emicizumab reached approximately 50 μg/mL at week 5, and were maintained above the therapeutic threshold (>30 μg/mL) thereafter. Laboratory tests for pharmacodynamic and safety biomarkers showed results consistent with previous studies.[10] Following the first emicizumab dose, aPTT shortened and remained within or below the reference range throughout the study. This shortening should not be considered indicative of normalization of hemostasis, as aPTT was shortened to within the normal range during the loading period, when emicizumab concentrations had not yet reached therapeutic levels. FVIII-like activity increased during loading and was maintained. No effect was seen on D-dimer and prothrombin time from emicizumab treatment, and levels remained stable throughout the study. A limitation of this study is the small population size (15 participants); for this reason, results should be interpreted with caution. Furthermore, the bleed and medication questionnaire that was used to report bleeds was completed by caregivers and was reliant on descriptions of symptoms from the child, which could have resulted in over- or under-estimation of bleeds. In conclusion, prophylaxis with emicizumab was well tolerated in Chinese children (aged <12 years) with HA and high-titer FVIII inhibitors, and safety findings were consistent with the known safety information available for emicizumab treatment. Emicizumab demonstrated substantial and clinically meaningful bleed control, similar to that observed in the adult/adolescent population of HAVEN 5 and in other Phase 3 studies. Acknowledgment The HAVEN 5 study was sponsored by F. Hoffmann-La Roche Ltd. The authors thank the study participants and their families, as well as the study investigators, research coordinators, and nurses. Third-party medical editing assistance, under the direction of the authors, was provided by Katie Smith, PhD, and Naziyat Khan, PhD, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd. Data sharing statement For up-to-date details on Roche’s global policy on sharing clinical information and how to request access to related clinical study documents, see https://go.roche.com/data_sharing. Anonymized records for individual patients across more than one data source external to Roche cannot, and should not, be linked because of the potential increase in risk of patient reidentification. Conflicts of interest RW declares no conflict of interest. JS declares no conflict of interest. QH declares no conflict of interest. CS is an employee and stockholder of F. Hoffmann-La Roche Ltd, and co-inventor of a patent related to an anti-FIXa/FX bispecific antibody. AK is an employee and stockholder of F. Hoffmann-La Roche Ltd. DL is an employee of Roche (China) Holding Ltd. YX is an employee of Roche (China) Holding Ltd. YZ is an employee of Roche (China) Holding Ltd. RY declares no conflict of interest.