Methodological recommendations for surgical care in patients with hemophilia A receiving prophylactic therapy with emicizumab. Recommendations of the expert group. Moscow, 2024.

Resolution by the Expert Council on the use of the Valoctocogene Roxaparvovec drug in patients with Hemophilia A in Russia.

Hemophilia B – a deficiency of blood coagulation factor IX (FIX) – is one of the most common hereditary coagulopathies along with hemophilia A and von Willebrand disease. As in hemophilia A, patients with hemophilia B require prophylactic treatment to prevent the development of bleeding and arthropathy, and there is a number of unsolved problems in their treatment. At the same time, the arsenal of drugs for the treatment of hemophilia B is significantly smaller compared to hemophilia A, and therefore the emergence of new drugs for the treatment of FIX deficiency is of great practical importance for doctors and patients. The article provides information about the pathogenesis and clinical course of hemophilia B, discusses the most promising areas in the treatment of this disease, such as innovative recombinant FIX molecules, rebalancing and gene therapy. In addition, we outlined clinical and laboratory criteria indicating the necessity to change treatment in patients with hemophilia B as well as presented clinical cases of patients who were switched to long-acting FIX products. The patients' parents gave their consent to the use of their children's data for research purposes and in publications.

Введение. Гемофилия — наследственное генетическое заболевание, связанное с дефицитом факторов свертывания крови, приводящим к кровотечениям различных локализаций. Основным принципом лечения гемофилии является специфическая заместительная терапия дефицитными факторами свертывания крови. Цель исследования: изучить динамику клинических и лабораторных показателей у пациентов с гемофилией А после перевода с лечения препаратами фактора свертывания крови VIII (FVIII) со стандартным периодом полувыведения на эфмороктоког альфа при наблюдении в течение 12 месяцев. Материалы и методы. В открытое многоцентровое несравнительное наблюдательное исследование в одной группе в условиях обычной медицинской практики были включены 30 пациентов в возрасте от 12 до 35 лет с гемофилией A любой тяжести, в возрасте от 12 до 33 лет, со среднегодовой частотой кровотечений ≥ 2, находящиеся на профилактической терапии препаратами FVIII на протяжении не менее одного года. Пациенты были разделены на 2 группы: 12–16 лет (n = 8) и 17–35 лет (n = 22). Для каждого пациента сбор данных проводился в рамках 5 визитов на протяжении 12 месяцев. Результаты. Лечение эфмороктокогом альфа, препаратом с пролонгированным периодом полувыведения, в течение 12 месяцев продемонстрировало улучшение клинических и лабораторных показателей у пациентов с гемофилией А, переведенных с лечения FVIII со стандартным периодом полувыведения. В возрастной группе 12–16 лет у 3 пациентов наблюдался как минимум один эпизод кровотечения, причем в течение первых 6 месяцев произошло в общей сложности 5 кровотечений. Среднегодовая частота кровотечений составила 0,6. В возрастной группе 17–35 лет у 10 пациентов наблюдался как минимум один эпизод кровотечения, в общей сложности 31 кровотечение за период исследования. Среднегодовая частота кровотечений составила 1,44. Серьезных нежелательных явлений зарегистрировано не было. Заключение. Положительная динамика наблюдалась уже в первые 6 месяцев исследования в обеих возрастных группах и включала изменения в частоте кровотечений, количестве инвазивных процедур и хирургических вмешательств, а также в состоянии суставов. Полученные результаты подтверждают высокую эффективность и безопасность эфмороктокога альфа при профилактическом лечении пациентов с гемофилией А. Introduction. Hemophilia is a hereditary genetic disease associated with a deficiency of blood clotting factors, which results in bleeding in various locations. The fundamental tenet of hemophilia treatment is specific replacement therapy with deficient blood clotting factors. Аim: to study changes in clinical and laboratory parameters in patients with hemophilia A after switching from standard half-life factor VIII (FVIII) preparations to efmoroctocog alfa for 12 months. Materials and Methods. An open, multicenter, non-comparative, observational single-arm study was conducted in a routine clinical setting. The study included 30 patients with hemophilia A of any severity aged 12 to 35 years with an average annual bleeding frequency of ≥ 2 episodes and prophylactic therapy with FVIII for at least one year. The patients were divided into two groups: 12–16 years (n = 8) and 17–35 years (n = 22). For each patient, data were collected during 5 visits over 12 months. Results. Treatment with fmoroctocog alfa, a prolonged-half-life agent, for 12 months resulted in improvements in clinical and laboratory parameters in patients with hemophilia A switched from a standard-half-life FVIII. In the 12–16-year age group, three patients experienced at least one bleeding episode, with a total of 5 bleeds occurring during the first 6 months. The mean annualized bleeding rate was 0.6. In the 17–35-year age group, 10 patients experienced at least one bleeding episode, with a total of 31 bleeds during the study period. The mean annualized bleeding rate was 1.44. No serious adverse events were reported. Conclusion. Positive changes were observed already in the first 6 months of the study in both age groups and included changes in bleedings frequency, the number of invasive procedures and surgeries, as well as improvements in joints condition. The results obtained confirm the high efficacy and safety of efmoroctocog alfa in the prophylactic treatment of patients with hemophilia A.

In our country, the use of emicizumab in children with hemophilia A without inhibitors (HA) in the real-world clinical setting is limited and is available only as few individual case reports. Our aim was to evaluate the effectiveness and safety of the prophylactic use of emicizumab in children with severe HA in the real-world clinical setting. We conducted a retrospective analysis of medical records of children with HA who had received emicizumab at 9 centers based in the Russian Federation. We assessed the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (ASBR), annualized joint bleeding rate (AJBR), annualized bleeding rate for bleeding episodes that required additional treatment with FVIII concentrate (ABRRT) and the number of hospital admissions for bleeding both before and after the treatment with emicizumab, as well as the occurrence and severity of adverse events during the therapy. Ethics committee approval was not required for this study because it involved the use of aggregated retrospective data from routine clinical practice that were fully anonymized. Two emicizumab administration regimens were compared with regard to their effectiveness. Before the treatment with emicizumab, ABR was 5.38 (95% confidence interval (CI) 3.90–7.64), ASBR – 4.16 (95% CI 2.99–5.94), AJBR – 2.7 (95% CI 1.87–4.03), and ABRRT – 4.8 (95% CI 3.37–7.08). After the initiation of the treatment with emicizumab, the bleeding rate plummeted: ABR decreased by 93.9% (95% CI 88.8–96.7), ASBR – by 96.9% (95% CI 93.1–98.6), AJBR – by 96.1% (95% CI 90.4–98.4%) and ABRRT – by 95.1% (95% CI 90.0–97.6). During the treatment with emicizumab, the rate of bleeding episodes that required hospital admission decreased from 1.58 (95% CI 0.98–2.68) to 0.04 (0.01–0.10), which amounted to 97.6% (95% CI 91.1–99.4). The median follow-up time for the patients treated with emicizumab was 15.5 months (range 9–29 months). When comparing the annualized bleeding rates in the groups of the patients who were preventively treated with emicizumab at doses of 3 mg/kg (administered once every 2 weeks) and 1.5 mg/kg (once per week), we didn't find any statistically significant differences. In the real-world clinical setting, the use of emicizumab in the children with HA led to a significant reduction in all bleeding episodes (by more than 90%), regardless of the administration regimen.

Introduction. In 2018 emicizumab was approved in Russia for prophylactic treatment in patients with hemophilia A (HA) with inhibitors and in 2019 for patients with severe HA without inhibitors. A significant amount of data has been accumulated from clinical trials and real-world data, which allow us to resolve most of the questions that hematologists may have when to prescribe emicizumab. Aim - to provide information on the management of patients on emicizumab. Results. The recommendations accumulated the currently available information and world experience in the management of patients receiving emicizumab in order to facilitate decision-making when prescribing and using emicizumab. Information on the use of emicizumab in patients with HA with FVIII inhibitors and severe HA without FVIII inhibitors is presented. Possible complications and measures for their prevention and treatment are presented.

Despite availability of prophylactic therapy for hemophilia A with factor VIII concentrates with a standard half-life, patients continue to experience episodes of bleeding and joint damage. The reasons for this may be the relatively short half-life of the factor VIII drug and the low adherence of patients to treatment. The appearance of clotting factor concentrates with an extended half-life makes it possible to reduce the frequency of infusions and increase the residual activity of the deficient factor. The article presents clinical observations of the use of Efmoroctocog alfa (recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc)) in a 16-year-old adolescent and a 7-year-old child with severe and moderate forms of hemophilia A. In order to select the most rational therapy regimen and evaluate the effectiveness of treatment, the authors have conducted individual assessments of patients’ pharmacokinetic (PK) parameters. The drug administration in both patients was twice per week. To assess individual PK, the WAPPS-Hemo was used in order to calculate individual PK parameters based on a small plasma samples collected during routine prophylactic treatment. During the PK study, 3 blood samples were taken to determine the level of factor VIII in a one-step method. In a 16-year-old patient, the half-life of Efmoroctocog alfa (t1/2) was 24.25 hours. The activity of factor VIII prior to the next injection was 7.4%. In addition, 81% of time the factor VIII activity was above 15%. In a 7-year-old patient, the t1/2 of the drug was 12.75 hours. The minimum residual activity of factor VIII was 2.1%, 86% of time the activity of factor VIII was above 3%. Conclusion: high efficacy and safety were demonstrated based on the results of the use of Efmoroctocog alfa in routine clinical practice in previously treated pediatric and adolescent patients with severe and moderate hemophilia A, as well as the reduction in the frequency of infusions per week from 3 to 2.

There are only limited data coming from isolated case reports regarding the real-world use of emicizumab for the treatment of children with hemophilia A and inhibitors (HAI) in Russia. The aim of the study was to evaluate the efficacy and safety of emicizumab prophylaxis in children with severe HAI. Ethical approval was not required since the study only involved the use of anonymized and generalized retrospective data obtained during routine clinical practice. We retrospectively analyzed medical records of children with HAI who had been treated with emicizumab at 11 institutions located in Russia, taking into consideration such parameters as annualized bleeding rates (ABR), annualized spontaneous bleeding rates (ASBR), annualized joint bleeding rates (AJBR) and annualized bleeding rates for bleeds requiring additional therapy (ABRRT), as well as the presence and severity of adverse events during the treatment. The median age of patients at the time of initiation of emicizumab prophylaxis was 65 (11–170) months. Before the treatment, ABR was 19.9 (95% confidence interval (CI), 15.4–26.1), ASBR – 13.6 (95% CI, 10.6–17.8), AJBR – 6.6 (95% CI, 4.7–9.7), ABRRT – 16.6 (95% CI, 12.4–22.7). After the initiation of the treatment, bleeding rates changed dramatically: ABR decreased by 98.6% (95% CI, 96.7–99.4), AJBR – by 99.4% (95% CI, 95.3–99.9), ABRRT – by 98.8% (95% CI, 96.8–99.6); and there were no signs of spontaneous bleeding during 10 (1–32) months of treatment. No adverse events leading to the interruption or discontinuation of the treatment with emicizumab were reported. The use of emicizumab in children with HAI in the real-world clinical setting results in a significant (> 98%) and safe reduction in bleeding episodes without any signs of spontaneous bleeding.

Цель исследования: сбор и анализ данных о результатах применения нонакога альфа (Иннонафактор) при лечении больных с тяжелой и среднетяжелой формой гемофилии B в возрасте от 12 лет и старше в условиях рутинной клинической практики. Материалы и методы. В проспективное многоцентровое открытое наблюдательное исследование был включен 51 пациент в возрасте от 16 до 59 (32,9 ± 9,5) лет. Среди них было 39 (76,5%) пациентов с тяжелой формой и 12 (23,5%) пациентов со среднетяжелой формой гемофилии В. Эффективность лечения оценивали по числу спонтанных кровотечений, возникших в течение 72–96 ч после введения нонакога альфа, их степени тяжести и числу инъекций для купирования одного эпизода кровотечения. Безопасность оценивали по частоте и характеру нежелательных явлений (НЯ). Результаты. В группепациентов, завершивших исследование по протоколу, зарегистрировано 41 (63%) спонтанное и 24 (37%) посттравматических кровотечения. Медиана (Ме) числа спонтанных кровотечений в течение 72–96 ч после введения нонакога альфа была равна 2, межквартильный диапазон (англ. interquartile range, IQR) –6. Средняя профилактическая доза составила 28,25 ± 12,24 МЕ/кг (Me = 26,3 МЕ/кг; IQR = 24,4 МЕ/кг). Для купирования возникших кровотечений на фоне профилактического лечения требовалось в среднем 1,9 ± 1,8 введения в средней разовой дозе 2137 ± 790 МЕ (Me = 2000 МЕ; IQR = 1000 МЕ). По результатам оценки реакции на лечение острого гемартроза по шкале Всемирной федерации гемофилии (англ. World Federation of Hemophilia, WFH) в группе профилактического лечения в 16 (32,0%) эпизодах реакция была оценена как «отличная», в 31 (62,0%) эпизоде — как «хорошая» и в 3 (6,0%) эпизодах – как «умеренная». В группе лечения по требованию в 10 (100%) эпизодах реакция была оценена как «хорошая». Было зарегистрировано 26 НЯ у 14 пациентов, из которых только 2 НЯ (дисгевзия и кашель) у одного пациента имели связь с применением нонакога альфа. Заключение. Полученные результаты свидетельствуют об эффективности и безопасности нонакога альфа как для профилактического лечения, так и для купирования возникших кровотечений у обследованных пациентов с тяжелой и среднетяжелой формой гемофилии B в условиях рутинной клинической практики. Objectives: to analyze the results of the nonacog alfa (Innonafactor) use in patients aged 12 years and older with severe and moderate hemophilia B in routine clinical practice. Patients/Methods. A prospective multicenter open, observational study included 51 patients aged 16 to 59 (32.9 ± 9.5) years. Among them 39 (76.5%) patients had severe hemophilia B and 12 (23.5%) patients had moderate hemophilia B. Treatment efficacy was assessed by the number of spontaneous bleedings occurring within72–96 hours after nonacog alfa administration, bleeding severity and number of injections to stop one bleeding episode. Safety was assessed by the frequency and type of adverse events (AEs). Results. Forty one (63%) spontaneous and 24 (37%) post-traumatic bleedings were registered in patients completed the study according to protocol. The spontaneous bleedings incidence was 2 (Me; IQR = 6) within 72–96 hours after nonacog alfa administration. The mean prophylactic dose was 28.25 ± 12.24 IU/kg (Me = 26.3 IU/kg; IQR = 24.4 IU/kg). About 1.9 ± 1.8 injections were required to stop a bleeding appeared during prophylactic treatment, an average single dose was of 2137 ± 790 IU (Me = 2000 IU; IQR = 1000 IU). Basing on World Federation of Hemophilia (WFH) scale the response to treatment of acute hemarthrosis was considered as “excellent” in 16 (32.0%), “good” in 31 (62.0%), and “moderate” in 3 (6.0%) for patients with prophylactic treatment, and as “good” in 10 (100%) in the on-demand treated group. AEs incidence was as 26 in 14 patients, of which only patient performed 2 AEs (dysgeusia and cough) associated directly with the nonacog alfa administration. Conclusions. The results lets know nonacog alfa as effective and safe for prevention and to stop bleedings in patients with severe and moderate hemophilia B in routine clinical practice.

The aim of the study was to evaluate the efficacy, safety and pharmacokinetics of nonacog alfa (Innonafactor) in children aged 2 to 12 years with hemophilia B. Materials and methods: 15 patients (7.7±2.5 years ) were included in an open, multicenter, prospective, non-comparative clinical trial, of whom 12 were aged 6 to 12 years and 3 were aged 2 to 6 years. The efficacy of the drug was assessed against the background of the introduction of 45±10 IU/kg 2 times a week with an interval of 72–96 hours, the safety was assessed by the frequency and nature of adverse reactions. Results: 5 (22%) spontaneous and 18 (78%) post-traumatic bleedings were registered. The mean number of spontaneous bleeding within 72 hours after administration of nonacog alfa was 2±1.4. The average prophylactic dose was 47.74±6.47 IU/kg (Me 48.2 IU/kg). An average of 2.2±2.1 injections was required to stop a bleeding episode. 19 adverse events have been reported that are not related to nonacog alfa. Conclusion: the obtained data indicate the efficacy and safety of nonacog alfa in the study group of patients. Thus, the data obtained indicate the efficacy and safety of Innonafactor drug both for prophylactic treatment and for the relief of bleeding in patients aged 2 to 12 years with severe and moderate hemophilia B.

Hemophilia B is a hereditary disease of the blood clotting system caused by a deficiency or molecular abnormalities of blood clotting factor IX. The main method of treatment is intravenous administration of coagulation factor IX concentrates. To optimize treatment and increase patient adherence to therapy, concentrates with a prolonged half-life have been developed.

Currently, the main method of treatment for hemophilia A is replacement therapy with drugs of blood coagulation factors VIII (FVIII). As a result of the development of new production technologies, recombinant FVIII are increasingly used for the treatment of hemophilia A. The justification for the use of new drugs in pediatric clinical practice requires careful preparation and clinical research studies of their efficacy and safety. The aim of this study was to evaluate the efficacy, safety and pharmacokinetics (PK) of domestic B-domain deleted recombinant factor VIII of Moroctocog alpha (Octofactor, GENERIUM JSC) in a cohort of children with hemophilia A aged 6 to 12 years in the framework of phase III clinical study of moroktocoga alpha in children 2 to 12 years old with hemophilia A. Materials and methods of the research: the age cohort of 6 to 12 years olds of an open multicenter prospective noncomparative study included 27 male children with severe hemophilia A (mean age 8,3±1,9 years). The study was carried out sequentially in 2 stages. Stage I included the study of PK parameters in 22 patients after a single study drug dose of 50 IU/kg. At stage II, the efficacy and safety of the drug was assessed in patients of stage I, as well as in additionally included 5 patients who received the study drug dose of 30±10 IU/kg per day every 2–3 days for 22±1 weeks of treatment. To assess the efficacy, we analyzed the incidence of spontaneous bleeding that occurred within 48–72 h after drug administration; the number of injections and the dose of FVIII used for prophylaxis, as well as for treatment on demand of one episode of bleeding, taking into account its severity; number of patients with severe hemophilia A with residual FVIII activity >/=1% 48–72 h after drug administration; the investigator's overall assessment of response to therapy on the acute hemarthrosis response scale. The main indicators for the analysis of PK properties were the area under the «concentration-time» curve, the half-life, the elimination constant, the increase in activity, and the degree of recovery of activity. To assess safety, the frequency of formation of an inhibitor to FVIII, the dynamics of vital and laboratory parameters, the frequency and characteristics of adverse events (AEs) associated with the administration of the drug were taken into account. Results: the area under the FVIII-time activity curve in the region of 0–48 h (AUC0-48) and with exponential extrapolation to infinity (AUC0-inf) was 731,82±264,94%*h and 756,11±270,16%*h, respectively. The half-life (T1/2) was 10,32±2,27 hours. In the examined age group, 78 bleeding were recorded, of which only 27 (35%) were spontaneous, including 24 (30%) episodes that occurred during 48–72 hours after the administration of drug under investigation. Haemorrhage within 48–72 hours after administration of the Octofactor drug was absent or was observed rarely (1–3 times) against the background of prophylactic treatment in most patients (88%), the median number of bleeding within 48–72 hours after administration of the study drug was 2 episodes per observation period. The proportion of spontaneous bleeding was the smallest in patients receiving a single prophylactic doses of the study drug 2000–3000 IU (7% of all bleeding), the largest proportion of spontaneous bleeding was observed in patients receiving a single prophylactic doses of the study drug 1000–2000 IU (70% of bleeding). The average single dose of Octofactor for preventive treatment was 1290,4±458,6 IU or 39,12±7,79 IU/kg, for on-demand treatment – 1641,7±722,4 IU per single injection. Of the 78 reported bleeding episodes, 68 (87%) required the study drug administration for relief, while the remaining 10 bleedings were selfcontained. On average, to stop bleeding, it took 1,5±0,8 injections of the drug on demand, median doses were 1 [1; 2], and average doses were 2434,3±1501,7 IU. During the study, 37 AEs were recorded in 15 (56%) patients. At the same time, 36 AEs (97%) were not associated with the drug under investigation, and one AE (allergic reaction), according to the researchers, was associated with the use of the drug. Thus, the analysis of data indicates the efficacy and safety of the Octofactor drug both the prophylactic treatment and treatment of on-demand bleeding in 6 to 12 year old patients with severe hemophilia A.

Hemophilia A is an X-linked congenital bleeding disorder caused by a deficiency or absence of coagulation factor VIII. In children who are in the first year of life, bleeding into the head accounts for 12.8–17.7 % of cases, and up to 45.5 % of them are intracranial bleeding in contrast to adult patients, in whom joints are the most frequent localization of bleeding. The first 2 years of life are the most dangerous in relation tointracranial bleeding for a child with hemophilia and the provision of full preventive treatment is extremely important for this time.Aim of the study – present the first experience of using emicizumab as primary prophylaxis in a child of the first year of life with hemophilia A. A patient born in 2020 with a severe hemophilia A had two post-traumatic bleeding that required hospitalization and replacement therapy. We decided to start primary prophylaxis with emicizumab at the age of 10 months.There were not spontaneous bleedings during 8 months of emicizumab usage. Post-traumatic bleeding did not require hospitalization and additional therapy.The clinical case demonstrates that emicizumab is effective and safe in infant who have not previously received prophylactic treatment.

Болезнь Виллебранда — наследственное заболевание свертывающей системы крови, обусловленное дефицитом или молекулярными аномалиями фактора Виллебранда (vWF). Верификация диагноза проводится на основе оценки данных семейного и личного анамнеза, клинических проявлений и результатов лабораторных исследований. Основной метод лечения — заместительная терапия — внутривенное введение препаратов vWF, содержащих vWF и фактор свертывания крови VIII (FVIII). Залогом успешного лечения пациентов с болезнью Виллебранда является подбор оптимального препарата с учетом индивидуальных потребностей пациента и фармакокинетических свойств концентратов Von Willebrand disease is a hereditary disease of blood coagulation system caused by a defi ciency or molecular abnormalities of von Willebrand factor (vWF). Verification of the diagnosis is based on the assessment of anamnesis, family and personal data, clinical manifestations and the results of complex laboratory tests. The main method of treatment is replacement therapy — intravenous administration of vWF concentrates containing blood coagulation factor VIII (FVIII) and vWF. The key to successful treatment of patients with von Willebrand disease is the selection of the optimal drug, taking into account the individual needs of the patient and the pharmacokinetic properties of the concentrates.

Под нашим наблюдением в клинике СПбГПМУ 2018 по 2019 г. находились 2 пациента детского возраста с болезнью Виллебранда (БВ) 3-го типа, которые нуждались в проведении оперативного лечения. Хирургическое вмешательство проводилось на фоне применения препарата Гемате П, который используется как для длительной, так и для краткосрочной профилактики при хирургических вмешательствах на фоне БВ. Использование препарата Гемате П было 100 % эффективным в обоих случаях.

Providing hemophilia patients with blood coagulation preparations is one of the priority tasks of the national health care system. In 2011, the first recombinant factor IX was created in Russia (rFIX, nonacog alpha, Innonafactor, GENERIUM JSC), that was previously studied for pharmacokinetic (PK) parameters, efficacy and safety in adult patients and adolescents over 12 years of age with severe and moderate hemophilia B. Objective of this open-label, prospective, multicenter, noncomparative clinical study was to study PK, efficacy and safety of Innonafactor in 12 patients aged 6 to 12 years with severe and moderate forms of hemophilia B (FIX activity less than 2%). The study included periods of screening, studies of PK parameters and treatment within 26±1 weeks, but not less than 50 days of administration of the studied drug. Nonacog alfa was administered in the study of PK parameters at a dose of 75 IU/kg, once, for prophylactic treatment – at a dose of 45±10 IU/kg, 2 times a week with an interval of 72–96 h. 30 minutes after administration of the studied drug, FIX activity increased to 73,93±13,35%, with a gradual decrease to 5,88±1,97% 72 hours after administration. The area under the «concentration ‒ time» curve in the section 0–72 h (AUC0–72) and with exponential extrapolation to infinity (AUC00‒∞) was 1573,41±407,16%*h and 1808,74 ± 437,59%*h respectively. Biological half-life (T1/2) was 28,11±8,60 hours. During preventive treatment there were 19 hemorrhagic episodes, 14 (74%) bleedings were post-traumatic and 5 (26%) bleedings were spontaneous. Mean number of bleeding episodes over the entire observation period was 1,9±1,4. Mean number of episodes of spontaneous bleeding that occurred within 72 hours after Innonafactor administration in patients with bleeding was 2,5±2,1. During the entire study period, patients received 942,5 thousand IU of the drug Innonafactor, 890,5 thousand IU were administered for prophylaxis and 52 thousand IU to stop bleeding on demand. Mean single dose of Innonafactor for prophylactic treatment was 46,24±5,86 IU/kg, for on-demand treatment – 49±13,1 IU/kg. Of the 19 registered bleeding episodes, 14 (73.7%) episodes required the administration of the studied drug; 5 (26,3%) bleedings stopped on their own. To stop one episode of bleeding, an average of 2,3±2,3 administration of nonacog alfa was required. At the end of the study, the proportion of hemophilia B patients with residual FIX activity of 2% or more was 92%. During the study, 14 adverse events (AEs) were registered in 7 (58,3%) patients. All reported AEs were not study drug related and did not require study drug withdrawal. Thromboembolic complications and immunogenic reactions were not registered. Thus, the data obtained indicate efficacy and safety of Innafactor both for prophylactic treatment and for on-demand treatment of bleeding in patients aged 6 to 12 years with severe and moderate hemophilia B.

Relevance. Immune tolerance induction (ITI) is the only approach proven to eradicate inhibitors in hemophilia A patients. ITI with Octanate® (human VWF-stabilized FVIII) has been shown to be effective at eradicating inhibitors, even in poor-prognosis patients. Here we report interim data from two observational, prospective studies on the use of Octanate® for ITI in patients in Russia.Purposes of research. The primary objective was to assess the efficacy of ITI. Secondary objectives included assessment of time to ITI success and inhibitor eradication.Patients and methods. Patients of any age with any severity of hemophilia A and a FVIII inhibitor  0.6 BU/mL were eligible. The ITI regimen was at the discretion of the treating physician.Results. The analysis included 73 patients. ITI outcomes were assessed in 63 patients who had completed the study, of whom 56 (89 %) had  1 poor prognostic factors. Inhibitor eradication was achieved by 77.1 % (37/48) of primary ITI patients and 71.4 % (45/63) of all patients, in a median of 2.4 months (range – 0.0–27.4) for both groups. Complete success was achieved by 72.9 % (35/48) of primary ITI patients in a median of 8.9 months (range – 2.4–28.0) and 66.7 % (42/63) of all patients in a median of 10.5 months (range – 2.4–28.0). No relapses were reported after complete or partial ITI success. Of the patients with  1 poor prognostic factors, 67.9 % achieved inhibitor eradication and 62.5 % complete success.Conclusions. ITI with Octanate® in a real-world setting showed rapid and sustained success, even in patients with poor prognostic factors.

Relevance.The development of a new recombinant blood coagulation factor VIII preparation is a promising step towards optimizing the treatment of hemophilia A. An introduction of a new medication into clinical practice precedes a clinical trials to evaluate the efficacy and safety.Materials and methods.The efficacy and safety of the domestic recombinant B-domain deleted blood coagulation factor VIII (FVIII) (moroctocog alfa, Octofactor®, JSC “GENERIUM”) were studied in the preventive treatment of 31 patients aged 21 to 52 years with severe haemophilia A. The Octofactor was administered in doses of 40 ± 5 IU/kg 3 times per week at intervals of at least 48 hours for 21 ± 1 weeks.Results.The efficacy of therapy was evaluated in 30 patients, since 1 patient refused to participate in the trial after the first injection of the study medication. There were registered 43 episodes of bleeding among 11 patients in the course of the preventive treatment with Octofactor. The average number of bleeding episodes was 1.4 ± 2.58. There were 43 bleeding episodes, 9 (20.9 %) of them were posttraumatic, 34 (79.1 %) of them were spontaneous. The average number of the spontaneous bleeding episodes (a major criterion of the efficacy) was 1.13 ± 2.19, which showed a low incidence of exacerbations of the hemorrhagic syndrome in the course of preventive treatment with Octofactor. Among all registered bleeding episodes there were 6 (14 %) mild episodes, 37 (86 %) moderate episodes. Among all spontaneous bleedings there were 6 mild episodes (17.6 %), 28 (82.4 %) moderate episodes. All posttraumatic bleedings were moderate. The vast majority (36, or 83.7 %) of bleeding episodes were stopped with administration of the Octofactor. The average number of administrations of the Octofactor for arresting 1 bleeding episode was 1.2 ± 0.56, for 1 spontaneous bleeding episode – 1.2 ± 0.59. On average, it was required to administer 3534.9 ± 2329.02 IU of the Octofactor to stop 1 episode of bleeding. In the vast majority of patients with severe hemophilia A (83.3–86.7 %), the remaining activity FVIII was 1 % or more after the administration of the Octofactor in 48 hours. The total amount of the Octofactor, introduced for the prevention of bleeding, was 6,107,000 IU, to stop bleeding – 152,000 IU. The safety of therapy was evaluated in 31 patients. There were recorded 25 adverse events (AE) in 17 patients. Among them the laboratory ones prevailed in 23 (92 %) cases, which is not associated with the use of the trial medication. There were noted nausea and an unpleasant aftertaste in the mouth in 1 patient during the first administration of the Octofactor, and therefore he refused to continue to participate in the trial. Causality 2 AE with the study drug was regarded as definite. Such AE are expected and described in the instructions to the preparation. All AE were not serious and mild and resolved without outcomes. There were no presented thromboembolic events and immunogenic reactions.Conclusions.The obtained data testify to the efficacy and safety of the Octofactor both for preventive measures and for stopping bleeding in adult patients with severe hemophilia A.

Результаты многоцентрового, проспективного, открытого, неконтролируемого исследования эффективности и безопасности препарата Иннонафактор у пациентов в возрасте 12 лет и старше с тяжелой и среднетяжелой гемофилией В