Low‐dose emicizumab for more equitable access to prophylaxis in resource limited countries

Abstract

This bispecific monoclonal antibody that mimics the coagulant activity of factor VIII (FVIII) has become a true game-changer in the management of haemophilia A (HA), making bleeding prophylaxis by subcutaneous injections a reality for all age groups, all degrees of FVIII deficiency and, most importantly, also for patients with FVIII inhibitors. These achievements are witnessed by a comprehensive phase 3 clinical development program that enrolled in the prospective HAVEN studies as many as 597 cases with and without inhibitor, with a spectrum spanning from infants (from birth to less than 12 months) to adolescents and adults with severe as well as mild or moderate FVIII deficiency.1, 2 In the HAVEN studies, emicizumab efficacy was demonstrated and approved by regulatory agencies for three maintenance dosing regimens, that is, 1.5 μg/kg once weekly, 3 mg/kg every two weeks and 6 mg/kg every 4 weeks. If to the pivotal HAVEN studies is added the phase 4 pharmacovigilance STASEY study,3 mainly designed to confirm safety and efficacy of emicizumab in a large cohort of 195 adults and adolescents with FVIII inhibitors, the total number of participants to the early clinical studies amounts to 792, that is the largest number of persons with a such rare disease as haemophilia ever enrolled in clinical studies. After its first licensing in 2018, the value of this medication was strengthened by subsequent real-world experiences in the frame of a large number of retrospective studies and cases series. It is currently estimated that more than 22,000 patients with HA are on prophylaxis with this drug, that is licensed in 120 countries and has generated sales as the 34th bestselling pharmaceutical in 20224 and an average annual growth of nearly 50% in the last 3 years. However, worldwide access to emicizumab is not uniform and lacks equity, being strongly related to per capita gross income of each country: the rate of full or partial access is 42.1% in high-income countries but 24.3% in upper middle-income countries, 25.2% in lower middle-income and as little as 7.5% in low-income countries. This unfair situation regarding access to this disruptive medication has prompted the World Federation of Haemophilia (WFH) in collaboration with the manufacturer to include emicizumab in the context of a humanitarian aid program implemented in low- and middle-income countries from Africa, Latin America, Asia and Eastern Europe, with the free distribution of as many as of 2258.730 mg of the drug. The impact of the WFH humanitarian program is much wider than only providing emicizumab.5 More than 28,000 patients with haemophilia A and B are being involved, of whom more than 4000 are on prophylaxis with replacement therapy but in at least 1155 cases from 34 countries prophylaxis is done with emicizumab used at the registered doses (loading dose of 3 mg/kg weekly for 4 weeks and maintenance of 1,5 mg/kg weekly, 3 mg/kg every 2 weeks and 6 mg/kg every 4 weeks). It can be understood why this medication is particularly cogent and appealing for access to haemophilia prophylaxis in low-income countries. In them, specialized treatment centres are scanty and often scattered at a great distances from where patients live. A drug that can be given once a month makes more feasible prophylaxis than coagulation factor products, which must be administered intravenously at relative short intervals and monitored for inhibitor development. The subcutaneous access route makes more feasible home treatment by patients themselves, rural doctor or relatives. In addition, the conditions for optimal storage of emicizumab are less stringent than those of traditional FVIII products, so that the need to attend the treatment centre for drug supply is more spaced. With this background, there are a number of published reports on the experiences gained in low- and middle-income countries in the attempt to reduce the conventional and approved dosage schedules of emicizumab and thus the costs of prophylaxis. The first report came from Malaysia and was presented as an abstract at ISTH 2021.6 After the traditional loading dosages, the authors managed to reduce the maintenance dosage regimens to 1.7–1.9 mg/kg, moving from once weekly to every other week and ultimately to once a month. This notwithstanding, the three cases in the series remained bleeding free, with the exception of a single episode of hematuria.6 A research letter from India published in 2023 reported a series of eight cases, of whom six had FVIII inhibitors and five of them, previously enrolled in the STASEY study, had received for 2 years standard loading and maintenance dosages of emicizumab.7 After the completion of the STASEY protocol, these cases were switched to low dosage maintenance regimens (.84–2.6 mg/kg), two of them every 3 weeks and three every 4 weeks. Patients were all bleed free for 52 weeks and thus were their own controls for the efficacy of low dosage regimens in comparison with the standard dosage regimens employed in STASEY. An important finding of this study is that the investigators measured with a reliable assay method the trough concentrations of plasma emicizumab in the context of the low dosage regimens. Trough values were in the range of 7.3–11.9 μg/mL, much lower than those measured at steady state with standard regimens in the HAVEN studies (ranging between 40 and 70 μg/mL). Thus, this study shows clearly that is possible to obtain satisfactory clinical responses employing much lower dosages and thus with significant cost reductions. A report8 from Thailand also supports the efficacy of low dose emicizumab. It was based on six patients on prophylaxis, with maintenance regimens spanning from 1.05 to 1.6 mg/kg every 4 weeks and the loading regimen was skipped. Monthly bleeding episodes decreased from 4−8 to 0−1 episodes, with a clinically relevant decrease of the ABR and AJBR. The most recent and largest report is again from Mumbai, India.9 In the frame of retrospective study design a reduced monthly maintenance dose of emicizumab (3 mg/kg) without loading dose was compared with low-dose FVIII (10–20 IU/kg, twice weekly) in two groups of 10 cases each. All clinical outcomes (number of target joints, annual bleeding rate and joint bleeding rate) were better, not only than before emicizumab prophylaxis but also in comparison with low-dose FVIII. The direct cost of low-dose emicizumab was similar to that of low-dose FVIII, but much lower than that of standard dosage emicizumab. In resource-limited countries, prophylaxis with low-dose factor concentrates has long been established as a preferred alternative to on-demand therapy. This minimal prophylaxis is actively recommended by the World Federation of Haemophilia. Unlike many therapeutic agents that do not allow dosage compromise (chemotherapies, anti-infectious agents, or metabolic disease controllers), haemophilia treatments provide major benefits even when they offer a minimum of haemostatic activity. Published experiences,6-11 the pharmacokinetic and pharmacodynamic properties of emicizumab, its ease of administration and ability to consistently convert severe haemophilia A into at least a moderate form are all arguments in favour of promoting low-dose emicizumab prophylaxis in resource-limited settings. Used at doses reduced by 50% or 25% or even less, emicizumab can double or quadruple the number of patients treated prophylactically. Thus, an unprecedented number of patients receiving prophylaxis in the history of this disease will be liberated and preserved from most of the immediate and delayed consequences of severe haemophilia A. The authors declare no conflicts of interest. This study did not receive specific funding. Not applicable

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