Enzyme replacement drugs for treatment of mucopolysaccharidosis type II (MPS II) do not penetrate the blood-brain barrier, significantly reducing their efficacy in patients with neuropathic form. Verenafusp alfa (Clotilia®) is a recombinant fusion protein of iduronate-2-sulfatase and a monoclonal antibody Fab fragment to human insulin receptor for distribution of the enzyme into brain. To evaluate safety, tolerability, and pharmacokinetic parameters of verenafusp alfa after single intravenous administration of escalating doses in healthy volunteers. This open-label, multicohort study included 20 healthy male volunteers aged 18 to 47 years (26.1±7.8 years). Verenafusp alfa was administered intravenously for 3 hours at single doses of 0.3 mg/kg (n=1), 0.5 mg/kg (n=1), 1 mg/kg (n=6), 2 mg/kg (n=6), and 3 mg/kg (n=6). Safety was assessed based on the incidence of clinical and laboratory adverse events (AEs) and their relationship to the investigational medicinal product. Pharmacokinetic parameters were calculated using a noncompartmental method. All 20 volunteers completed the study. AEs reported in 6 (30%) volunteers were mild in severity and related to changes in individual laboratory and instrumental test data. One AE (increased bilirubin level) was possibly related to the study drug. Pharmacokinetic analysis demonstrated a dose-dependent increase in maximum concentration (Cmax) from 197.60 (0.3 mg/kg) to 10,225.80 ng/mL (3 mg/kg) and area under the concentration-time curve (AUC) from 38,678.60 to 2,714,067.42 ng×min/mL respectively. The half-life ranged from 86.69 to 213.42 minutes, and clearance lowered with the increasing dose from 7.67 to 1.11 mL/min/kg. Single intravenous administration of verenafusp alfa at doses ranging from 0.3 to 3 mg/kg demonstrated a favorable safety profile and good tolerability in healthy volunteers. The drug's pharmacokinetics was nonlinear, with a dose-dependent increase in Cmax and AUC with the dose increment. Volume of distribution volume lowered with increase of the dose. Введение. Используемые ферментные препараты для лечения мукополисахаридоза II типа не способны проникать через гематоэнцефалический барьер, что существенно снижает их терапевтическую эффективность при нейропатической форме заболевания. Веренафусп альфа (Клотилия®) представляет собой рекомбинантный гибридный белок, состоящий из идуронат-2-сульфатазы и Fab-фрагмента моноклонального антитела к инсулиновому рецептору человека, способный проникать через гематоэнцефалический барьер. Цель. Оценить безопасность, переносимость и фармакокинетические параметры веренафуспа альфа при однократном внутривенном введении в возрастающих дозах у здоровых добровольцев. Материалы и методы. В открытое мультикогортное исследование включены 20 здоровых мужчин-добровольцев в возрасте 18–47 лет (26,1±7,8 года). Веренафусп альфа вводили однократно внутривенно в течение 3 ч в дозах 0,3 мг/кг (n=1), 0,5 мг/кг (n=1), 1 мг/кг (n=6), 2 мг/кг (n=6), 3 мг/кг (n=6). Безопасность оценивали по частоте клинических и лабораторных нежелательных явлений (НЯ) и их связи с исследуемым препаратом. Фармакокинетические параметры рассчитывали некомпартментным методом. Результаты. Все 20 добровольцев полностью завершили исследование. Зарегистрированные у 6 (30%) человек НЯ были легкой степени тяжести и относились к изменениям индивидуальных данных лабораторных и инструментальных исследований. Одно НЯ (повышение уровня билирубина) имело возможную связь с исследуемым препаратом. Фармакокинетический анализ продемонстрировал дозозависимое увеличение максимальной концентрации от 197,60 (0,3 мг/кг) до 10 225,80 нг/мл (3 мг/кг) и площади под кривой «концентрация–время» от 38 678,60 до 2 714 067,42 нг×мин/мл соответственно. Период полувыведения составил от 86,69 до 213,42 мин, клиренс снижался с увеличением дозы от 7,67 до 1,11 мл/мин/кг. Заключение. Однократное внутривенное введение веренафуспа альфа в дозах 0,3–3 мг/кг продемонстрировало благоприятный профиль безопасности и хорошую переносимость у здоровых добровольцев. Фармакокинетика препарата была нелинейной и характеризовалась уменьшением объема распределения и непропорциональным увеличением максимальной концентрации и площади под кривой «концентрация–время» с возрастанием дозы.

Leukodystrophies (LDs) are a group of rare, genetic disorders unified by their hallmark involvement of the cerebral white matter. They are typically characterized as progressive disorders, resulting in severe neurologic decline and premature death within months to years after onset. Managing LDs therefore requires lifelong, multidisciplinary care, a challenge compounded by their rarity and phenotypic heterogeneity, for which detailed clinical and scientific information is sometimes lacking. Research networks have proven useful in the rare disease community to unite efforts, increase awareness, and accelerate progress toward understanding and treating these often understudied conditions. Therefore, we established the Canadian Association for Research Excellence in Leukodystrophy (CARELeuko), a national network dedicated to improving LD care, research, and treatment within Canada. To better understand and address the most pressing needs for LDs in Canada, we engaged a diverse group of stakeholders including researchers, clinicians, and patient advocates to highlight and prioritize gaps in LD care and research. In this review, we discuss the key gaps identified in the Canadian LD landscape and outline strategies to address these challenges. This effort will inform the development of targeted initiatives aimed at improving outcomes for Canadian families affected by these debilitating disorders.

Mucopolysaccharidosis type II (MPS II) is a chronic inherited disease with multiorgan involvement, a progressive course, and restricted life expectancy. To evaluate the predictors of fatal outcomes in MPS II patients. In the retrospective cohort study, the clinical, laboratory data and enzyme replacement therapy (ERT) (84.2%) of about 160 patients were extracted and analyzed from the Russian MPS II registry, with death as a primary outcome. We compared patients who died (n = 20; 12.5%) with severe form (n = 13; 68.4%) and attenuated form (n = 6, 31.6%) to 140 alive patients. Fatal outcomes occurred in 5%, 35%, 20%, and 40% of patients before 10, 10-14, 15-19, and ≥ 20 years. The most common causes of death were cardiovascular (29.4%), respiratory failure (17.6%), including pneumonia (17.6%), and their associations (17.6%) and MPS II progression (11.8%). Acute or chronic respiratory failure was in 53%. Died patients had higher birth weight, higher age of diagnosis, and start of ERT. Hydrocephalus, hydrocephalus bypass surgery, epilepsy, difficulty swallowing, and impaired movement after 12 years of age were significantly more common in the deceased patients. Cox regression analysis has revealed the following time-dependent covariates of the lethal outcome: 1st-year psychomotor development delay, delayed mental and speech development, hydrocephalus, swallow disorders, impossible walking at age > 12 years, respiratory disorders, tracheostomy, neuronopathic form. Increased birth weight, delayed diagnosis and the start of ERT, and development of neuronopathic form with impossible walking after 12 years were the main predictors of the fatal outcome.

Allogeneic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for patients with mucopolysaccharidoses (MPS). We investigate the efficacy and improvements in the quality of life of HSCT in pediatric patients with MPS. A retrospective analysis of transplantation data from 46 cases of MPS from a single institution in China was conducted. The cohort of 46 patients included 9 cases of MPS I, 16 cases of MPS II, 15 cases of MPS IVA and 6 cases of MPS VI. The median age at diagnosis was 2.59 years. The median age at transplantation was 3.80 years. The median follow-up time was 3.1 years (range, 0.8-8.1 years) and 43 patients were alive. The incidence of grades II to IV aGVHD was 17.4%, wherein the incidence of grades III and IV aGVHD was 4.3%. The incidence of moderate-to-severe cGVHD was 6.5%. GAGs urinary excretion decreased and enzyme activity levels reached normal. After HSCT, multiple bone dysplasia, upper-airway obstruction and recurrent otitis media were significantly improved; vision, corneal clouding, cardiovascular disease, hepatosplenomegaly and hydrocephalus were improved or remained stable; neurological symptoms were improved or remained stable in most patients but progressed in others; the patients with MPS IH/S and MPS II reached nearly normal growth rate of height and weight. Meanwhile, the patients with MPS IH, MPS IVA and MPS VI remained poor growth after HSCT. The Activities of Daily Living (ADL) scores were improved in most patients with MPS. ADL scores in patients with severe phenotypes were lower than health control subjects and patients with attenuated phenotypes. HSCT is a good therapeutic option for MPS and improves the quality of life of patients. MPS patients with attenuated phenotypes provide a better outcome in ADL after HSCT.

Mucopolysaccharidosis II (MPS II) is a rare, progressive, X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase has been approved for the treatment of patients with MPS II since 2005. The Hunter Outcome Survey (HOS; NCT03292887) was established as a condition of approval to monitor the long-term safety and effectiveness of idursulfase. Here, we report the final results from HOS. HOS was a multicenter, long-term, observational registry that enrolled patients with a biochemically and/or genetically confirmed diagnosis of MPS II who were untreated or treated with idursulfase and/or bone marrow transplant. Patients were enrolled prospectively (alive at enrollment) and retrospectively (deceased at enrollment). For prospectively enrolled patients, it was requested that data from routine examinations were recorded after each follow-up visit and/or a minimum of every 6 months. The safety population (SP) included patients who received at least one dose of idursulfase and were alive at HOS entry. The treatment outcomes population (TOP) included patients who received at least one dose of idursulfase and were alive at HOS entry, excluding patients who received a bone marrow transplant, patients for whom an informed consent form could not be generated by the center, and patients with a missing date of birth. Safety and effectiveness endpoints were analyzed with descriptive statistics. In total, 1332 patients were enrolled in HOS. For patients in the SP (N = 1014), the median (10th percentile, 90th percentile) age at initiation of ERT with idursulfase was 5.7 (1.6, 18.1) years, ranging from 0.0 to 65.5 years. In the TOP (N = 989), a consistent and sustained decline in urinary glycosaminoglycan levels, trends of sustained improvements in walking capacity and left ventricular mass index, and reductions in liver and spleen size were observed. Treated patients also demonstrated a median increase in survival time of approximately 10 years and a 57.9 % lower risk of death compared with an unmatched cohort of untreated patients. In the SP, 691 patients (68.1 %) experienced at least one adverse event and 269 (26.5 %) experienced at least one infusion-related reaction (IRR); most were mild or moderate in severity. There was no relationship observed between anti-drug antibody status and IRR rates. Data from HOS, collected for over 18 years, represent the largest dataset of patients with MPS II to date. The effectiveness and safety profile of idursulfase support its use for the long-term treatment of patients with MPS II.