Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A.

INTRODUCTION: SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which full-length recombinant (r) FVIII (anti-haemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer. AIM: To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25-75 IU/kg in patients with severe haemophilia A (FVIII activity <1%). METHODS: Multinational, phase 1, prospective, open-label, two-period, fixed-sequence, dose-escalation trial (clinicaltrials.gov NCT02716194). Patients received single doses of rFVIII and then SHP656 sequentially at the same dose: 25 ± 3 IU/kg (Cohort 1), 50 ± 5 IU/kg (Cohort 2) and 75 ± 5 IU/kg (Cohort 3). RESULTS: Forty patients received rFVIII: 11 in Cohort 1, 16 in Cohort 2 and 13 in Cohort 3. Two patients withdrew before receiving SHP656, leaving 38 patients who completed the study and received both treatments. No treatment-related adverse events (AEs), serious AEs, deaths, study withdrawals, thrombotic events or allergic reactions were reported; and no significant treatment-related changes in laboratory parameters or vital signs. No patients developed FVIII inhibitors or antibodies to PSA. FVIII activity was significantly prolonged following SHP656 administration vs rFVIII with an approximately 1.5-fold extension in mean residence time (P < .05). Exposure increased proportional to the SHP656 dose over the 25-75 IU/kg dose range. CONCLUSION: Polysialylation of rFVIII confers a half-life extension similar to that of approved extended half-life products that use either PEGylation or Fc fusion technology and was not associated with any treatment-related adverse events.

von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease.

ABSTRACT: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

Benthic fauna in the south-eastern part of the Pechora-sea: Current state and analysis of ecological quality.

In recent decades, economic activity has sharply increased in the Pechora Sea, one of the most hydrologically unique areas of the Barents Sea. Hence, the information about the current state of its ecosystems is quite important for assessing their possible changes in the future. The aim of the present study was to analyze the distribution of macrobenthos and assess its ecological quality in the southeastern part of the Pechora Sea at the beginning of the 21st century (based on data collected in 2012-2013). The results showed that since 1920s there have been no serious changes in the macrobenthos in the studied area. The weak shifts detected in the benthic fauna were either within the natural range of fluctuations in population of common species, or may be associated with differences in the methodological approaches of different researches. Heterogeneity in the macrobenthos distribution, the most significant abiotic factors identified in relation to it, quantitative indicators of biota, and species dominating in communities were similar to those revealed in previous studies. As of 2013, the characteristics of benthic communities in the southeastern part of the Pechora Sea, including their ecological quality, allow us to refer them as undisturbed biosystems.

Medical Care for Tuberculosis-HIV-Coinfected Patients in Russia with Respect to a Changeable Patients' Structure.

To date, tuberculosis (TB) remains the primary cause of mortality in human immunodeficiency virus (HIV) patients in Russia. Since the beginning of 2000, a sharp change in the HIV patients' structure, to the main known risk factors for HIV infection has taken place in Russia. The transmission of HIV through injectable drug use has begun to decline significantly, giving way to the prevalence of sexual HIV transmission today. These changes may require adjustments to organizational approaches to anti-TB care and the treatment of HIV-positive patients. Our study is aimed at identifying changes in TB-HIV coinfection patients' structures in 2019 compared to 2000. Based on the results obtained, our goal was to point out the parameters that need to be taken into account when developing approaches to improve the organization of TB control care for people with HIV infection. We have carried out a cross-sectional, retrospective, epidemiological study using government TB registry data from four regions in two federal districts of Russia in 2019. The case histories of 2265 patients from two regions with high HIV prevalence, which are part of the Siberian Federal District of Russia, and 89 patient histories from two regions of low HIV prevalence, which are part of the Central Federal District of Russia, were analyzed. We found that parenteral transmission (69.4%) remains the primary route of HIV transmission among the TB-HIV coinfected. The unemployed of working age without disability account for 80.2% of all coinfected people, while the formerly incarcerated account for 53.7% and the homeless account for 4.1%. Those with primary multidrug-resistant TB (MDR-TB) comprise 56.2% of HIV-TB patients. When comparing the incidence of coinfection with HIV among TB patients, statistically significant differences were obtained. Thus, the chances of coinfection increased by 4.33 times among people with active TB (95% CI: 2.31; 8.12), by 2.97 times among people with MDR-TB (95% CI: 1.66; 5.32), by 5.2 times in people with advanced processes in the lungs, including destruction, (95% CI: 2.78; 9.7), as well as by 10.3 times in the case of death within the first year after the TB diagnosis (95% CI: 2.99; 35.5). The absence of data for the presence of TB during preventive examination was accompanied by a decrease in the chances of detecting coinfection (OR 0.36; 95% CI: 0.2; 0.64). We have identified the probable causes of the high incidence of TB among HIV-infected: HIV-patient social maladaptation usually results in delayed medical care, leading to TB treatment regimen violations. Furthermore, self-administration of drugs triggers MDR-TB within this group. Healthcare providers should clearly explain to patients the critical importance of immediately seeking medical care when initial TB symptoms appear.

COVID-19 in Dental Settings: Novel Risk Assessment Approach.

The novel coronavirus (COVID-19) outbreak is a public health emergency of international concern, and this emergency led to postponing elective dental care procedures. The postponing aimed to protect the public from an unknown risk caused by COVID-19. At the beginning of the outbreak, for public health authorities, the aerosol-generating procedures and the close proximity between dental care workers and patients in dentistry represented sufficient justification for the delay of dental visits. Dental care is a priority, and for many years, studies have proven that the lack and delay of dental care can cause severe consequences for the oral health of the general population, which can cause a high global burden of oral diseases. Safety is necessary while resuming dental activities, and risk assessment is an efficient method for understanding and preventing the COVID-19 infectious threats facing the dental industry and affecting dental care workers and patients. In this study, for safe dental care delivery, we adapted risk assessment criteria and an approach and an occupational classification system. Based on those tools, we also recommend measures that can help to minimize infectious risk in dental settings.

Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort.

BACKGROUND: Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors. OBJECTIVES: To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors. PATIENTS/METHODS: In this open-label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once-monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient-reported outcomes (exploratory). RESULTS: The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean [SEM]) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean [standard deviation] 69.4 [16.3] days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (-9.2 [2.9]) and physical health (-12.3 [3.9]) domain scores suggested clinically meaningful improvement. CONCLUSIONS: Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.

Phase 3 Clinical Trial: Perioperative Use of Nonacog Gamma, a Recombinant Factor IX, in Previously Treated Patients With Moderate/Severe Hemophilia B.

Hemostatic management is essential for ensuring the safety of patients with hemophilia during surgery. This phase 3, prospective, uncontrolled trial, evaluated hemostatic efficacy, consumption, and safety of a recombinant factor IX concentrate, nonacog gamma (BAX 326, Rixubis® [Baxalta US Inc., a Takeda company, Lexington, MA, USA]), in intraoperative and postoperative settings in previously treated patients (PTPs) with severe or moderately severe hemophilia B undergoing elective surgery (N = 38 surgeries; 21 major, 17 minor). Predefined preoperative hemostatic factor IX levels (80-100% of normal for major and 30-60% for minor surgeries) were maintained for each patient. Intraoperative efficacy was rated as "excellent" or "good" for all surgeries. Postoperative hemostatic efficacy on day of discharge was rated as "excellent," "good," and "fair," respectively, for 29 (76.3%), 7 (18.4%), and 2 (5.3%) surgical procedures. All adverse events were considered unrelated to study drug; most frequently reported was mild procedural pain (9 patients). No thrombotic events, severe allergic reactions, or inhibitor formation were observed. Nonacog gamma was well tolerated and effective for intraoperative and postoperative hemostatic management of PTPs with hemophilia B.NCT01507896, EudraCT: 2011-000413-39.