Nonreplacement therapy for hemophilia in low-income countries: experience from a prospective study in Ivory Coast

Background Hemophilia management has fundamentally evolved over the last decades with the development of ground-breaking therapies. Because of their mode of action and biochemical properties, these innovative therapies that are available in developed countries could be readily implemented among people from low-income countries who are either not or inadequately treated with clotting factor concentrates (CFCs). Objectives We aimed at evaluating the impact of prophylaxis with emicizumab, a bispecific monoclonal antibody mimicking the FVIII activity administered subcutaneously, among boys with severe hemophilia A (HA) from the Ivory Coast, where access to CFCs is limited to humanitarian aid. Methods We prospectively collected data on the implementation and outcomes of prophylaxis with emicizumab, in 33 Ivorian boys aged 2 to 13 years with severe HA (with and without inhibitors). Bleeds, CFC consumption, quality of life and satisfaction of the patients and their parents were assessed. Results Overall, 12 months after initiating emicizumab, a 99% reduction in bleeding rates was observed, with a raise from 18% to 100% of boys having zero spontaneous joint bleeds. Three boys required a single FVIII infusion following a traumatic bleed. Health-related quality of life measures significantly improved, and perception of treatment efficacy was positively rated in children and parents. Acceptance, tolerance, and adherence were excellent. Emicizumab was instrumental in successfully implementing uninterrupted, highly efficacious, and well-tolerated prophylaxis in 72% of the Ivorian children aged ≤ 13 years identified with severe hemophilia A. Conclusion These data illustrate how innovative and disruptive nonreplacement therapies that are already accessible in developed countries could potentially provide equity in care by profoundly and rapidly modifying hemophilia burden with a magnified impact in low-income countries.

more promising aspect is that these new therapies, because of their favorable profile, can be implemented readily among the hundreds of thousands of HA patients who are currently not being treated or are inadequately with CFCs worldwide. [1] We herein report the experience of implementing treatment with emicizumab, a subcutaneously administered humanized bispecific mAb mimicking the function of FVIII, to treat young boys with severe HA in the Ivory Coast. These data demonstrate the huge potential of such revolutionary therapeutic options to treat rare diseases like hemophilia in resource-constrained countries.

| C O N T E X T
This initiative took place in a Sub-Saharan African country where access to diagnosis and appropriate hemophilia management remain challenging and where CFCs available in limited amounts are exclusively issued from the WFH Humanitarian Aid Program. Over the last years, awareness and management of hemophilia have gradually improved in the Ivory Coast thanks to WFH initiatives including an active twinning program and the initiation of a low-dose and low-frequency prophylaxis program in children with donated CFCs. [9] This eventually led to the recognition of hemophilia as a major health issue by the local health authorities in 2021. Following a coinvestment agreement between F.
Hoffmann-La Roche Ltd and the Ivorian government, access to emicizumab was made possible in April 2021. The drug was granted a temporary marketing authorization, being provided free of charge in limited but sufficient amounts to treat children in priority. In June 2021, 46 children aged ≤13 years with severe HA had been identified across the country. All were regularly followed-up at the hemophilia treatment center (HTC) of Yopougon in Abidjan, the only HTC in the country.

| M E T H O D S
For the purpose of rigorous and objective documentation, a prospective study was set up with the aim of collecting data on implementation and outcomes of prophylaxis with emicizumab among Ivorian boys with severe HA. The inclusion criteria were as follows: boys aged 2 to 13 years with severe HA, with or without inhibitors,

Essentials
• New hemophilia treatment options are currently mainly available in high-income countries.
• A majority of people with hemophilia worldwide still have no access to appropriate care.
• We studied how access to emicizumab modified the burden of hemophilia in boys from Ivory Coast.
• The impact of innovative hemophilia therapies is magnified in low-income countries. regularly followed at least for 12 months at the HTC of Abidjan, and whose parents agreed to participate and were willing to perform prophylaxis. Emicizumab was delivered at the HTC in Abidjan and initially administered at the HTC or the proximity hospital. Following education of the parents, home therapy was allowed. A rescue dose of CFC (Fc-rFVIII-efmoroctocog alfa) was provided to each participant to treat potential breakthrough bleeding episodes without any delay.
Data on bleeds, FVIII consumption, as well as number of days of hospitalization and absence from school were collected both from patients' logbooks and during the follow-up visits. Data were gathered retrospectively 12 months before inclusion and prospectively during a 12-month follow-up period. Activated partial thromboplastin time

| Statistical analysis
All analyses were performed using the JMP Pro software Version 14.3.0 (100 SAS Campus Drive Cary, USA). Continuous variables were expressed either as means and standard deviations or as medians and ranges and compared between groups using the Wilcoxon rank-sum test. Nonparametric paired tests were used to compare 2-time points. Categorical variables were expressed as counts and percentages and compared between groups using the Pearson chi-squared test. Statistical significance was set at P <0.05.

| Role of the funding source
This study did not receive any financial support.

| Demographics
Overall, 37 boys aged 2 to 13 years with severe HA and followed-up at the HTC of Yopougon in Abidjan were identified as potential participants. Among them, 33 were enrolled and started prophylaxis with emicizumab (3 mg/kg/week for 4 weeks followed by 6 mg/kg/28 days [11]) between July and October 2021. A whole vial of emicizumab was administered with a dose rounded (±2.5 kg) as close as possible to the weight. Reasons for exclusion were parental refusal (n = 2), lack of adherence during the 12 months before screening (n = 1), and overweight (n = 1, aged 12 years and on low-dose prophylaxis with CFCs, as the amount of emicizumab was limited). The chosen treatment regimen allowed for fewer visits to the HTC as half of the participants lived in remote areas. All participants were followed prospectively at the HTC every 4 weeks for the first 6 months. At the end of this period, visits interval could be spaced at 2 months in participants whose parents were able and willing to inject emicizumab. The demographic characteristics of the study population are detailed in Table 1. Of note, at inclusion, 42% of patients were on the low-dose prophylaxis program with Fc-rFVIII issued from the WFH Humanitarian Aid Program for 3 years. However, because of interruptions in supply and donations during the COVID-19 pandemic, prophylaxis T A B L E 1 Demographic characteristics of the 33 boys with severe hemophilia A at inclusion (T0

| Prophylaxis outcomes
The outcomes of emicizumab prophylaxis are summarized in Tables 2   and 3. After 12 months, a dramatic 99% reduction of the estimated annualized bleeding rate (ABR) was observed in the study population.
The proportion of boys with no spontaneous joint bleeds rose from 18% to 100%. Three boys, without inhibitors, experienced a traumatic bleed (skin and tongue wound) that was successfully treated using a single injection of Fc-rFVIII (1000 IU for two of them and 2000 IU for the last one). No hospitalization was required, and only two boys who

| D I S C U S S I O N
In low-income countries, where 70% of PWH live, very few individuals have access to adequate diagnosis and treatment, resulting in a high morbidity and mortality often early in life. The limited local resources available are indeed being allocated to multiple public health priorities, such as nutrition, immunization, sanitation, and treatment of infectious diseases, rather than to hemophilia. [12] In addition to very limited access to CFCs, poor awareness of hemophilia, scarce laboratory diagnostic capabilities, limited number of HTCs and experienced staff, costs related to travels to the HTCs, storage challenges, and expenses for disposables and CFCs infusions represent additional obstacles to hemophilia care and treatment in low-income countries.
[12] The situation is even worse for patients with neutralizing antibodies against CFCs who do not have access to bypassing hemostatic agents or immune-tolerizing treatments.
Fortunately, the situation in the Ivory Coast has recently improved, with a significant number of PWH now having access to These data illustrate in a very original way how highly innovative and ground-breaking therapies currently accessible in developed countries can potentially provide equity in care globally by profoundly and rapidly modifying the burden of a rare disease with a magnified impact in low-income countries.