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.
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.
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.
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 .).
Summary
Extended half‐life proteins (EHL) are increasingly used in clinical practice, but there is no standardized approach to sampling, interpretation and implementation of pharmacokinetics (PK) ...data to maximize treatment benefit. The goal of EHL treatment is to attain a trough level sufficient to protect against spontaneous bleeds and reduce infusion frequency and limitations on individual activity and lifestyle. Performing classical PK assessments requires multiple blood samples, which is burdensome for patients and providers. Herein we review a population pharmacokinetic (popPK) approach to estimate individual PK parameters to transition patients from standard half‐life (SHL) to EHL concentrates. We propose that a minimum of two to four post‐infusion samples is sufficient to estimate individual PK profiles, with sufficient certainty to maintain factor levels above 1% and achieve bleed‐free lifestyles. We also survey current PK use in patients transitioning to EHL, review key PK parameters and popPK models, and recommend an approach to using PK in patients initiating or switching to EHL.
Summary
Introduction
von Willebrand factor (VWF) plays a critical role in platelet adhesion and aggregation after vascular injury and at sites of high shear rate. Elevated VWF levels are associated ...with an increased risk of ischemic cardiovascular events; however, it is unclear whether VWF deficiency is protective against atherosclerosis. We aimed to compare the prevalence of cardiovascular disease (CVD) among patients with and without von Willebrand disease (VWD).
Methods
A cross‐sectional analysis was performed on discharge data for adults from the Nationwide Inpatient Sample (NIS) between the years 2009 and 2011. CVD was defined as ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, or peripheral vascular disease. For prevalence calculations and statistical analyses, we used discharge‐level weights provided by the NIS to reflect national estimates. CVD was compared across groups by use of the Rao–Scott chi‐square test. Multivariable logistic regression was used to estimate the likelihood of CVD in VWD patients after adjustment for age, gender, and CVD‐related risk factors.
Results
The prevalence of CVD in VWD patients was less than the prevalence of CVD in non‐VWD patients (15.0% versus 26.0%). VWD was associated with a decreased likelihood of CVD after adjustment for age, gender, and CVD‐related risk factors (odds ratio 0.85; 95% confidence interval 0.79–0.92).
Discussion
These findings indicate that the risk of CVD is decreased among VWD patients, and that VWF deficiency may be protective against CVD.
Introduction: A pulmonary embolism (PE) is a leading cause of mortality in hospitalized patients, yet the prevalence of PE in sickle cell disease (SCD) and its relation to disease severity or ...intrinsic hypercoagulability are not established.
Methods: We estimated inpatient PE incidence and prevalence among SCD and non‐SCD populations in Pennsylvania, and compared severity of illness and mortality, using Pennsylvania Health Care Cost Containment Council (PHC4) discharge data, 2001–2006. Risk factors for PE were assessed in a case–control study of discharges from the University of Pittsburgh Medical Archival Records System (MARS).
Results: The incidence of inpatient PE was higher in the SCD PA population than in the non‐SCD Pennsylvania population, 2001–2006. The PE prevalence among SCD discharges ≤ 50 years of age, 0.57%, was similar to that in non‐SCD Pennsylvania discharges, 0.60%, and unchanged after adjustment for race. Among SCD discharges, those developing PE were significantly older, with a longer length of stay, greater severity of illness and higher mortality, P < 0.001, than SCD without a PE. Among PE discharges, SCD had a similar severity of illness, P = 0.77, and mortality, P = 0.39, but underwent fewer computerized tomographic scans, P = 0.006, than non‐SCD with PE. In the local case–control study, no clinical or laboratory feature was associated with PE.
Conclusions: The incidence of PE is higher and chest computed tomography (CT) utilization is lower in SCD than non‐SCD inpatients, suggesting that PE may be under‐diagnosed.
We present the results of the one-year long observational campaign of the type II plateau SN 2005cs, which exploded in the nearby spiral galaxy M51 (the Whirlpool galaxy). This extensive data set ...makes SN 2005cs the best observed low-luminosity, 56Ni-poor type II plateau event so far and one of the best core-collapse supernovae ever. The optical and near-infrared spectra show narrow P-Cygni lines characteristic of this SN family, which are indicative of a very low expansion velocity (about 1000 km s−1) of the ejected material. The optical light curves cover both the plateau phase and the late-time radioactive tail, until about 380 d after core-collapse. Numerous unfiltered observations obtained by amateur astronomers give us the rare opportunity to monitor the fast rise to maximum light, lasting about 2 d. In addition to optical observations, we also present near-infrared light curves that (together with already published ultraviolet observations) allow us to construct for the first time a reliable bolometric light curve for an object of this class. Finally, comparing the observed data with those derived from a semi-analytic model, we infer for SN 2005cs a 56Ni mass of about 3 × 10−3 M⊙, a total ejected mass of 8–13 M⊙ and an explosion energy of about 3 × 1050 erg.
Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (F.IX) into skeletal muscle results in ...sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2×1011 vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of F.IX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease.
Fitusiran is an RNA interference therapeutic that targets antithrombin (AT) in the liver and interferes with AT translation by binding and degrading messenger RNA-AT, thereby silencing AT gene ...expression and preventing AT synthesis. In both preclinical and clinical studies, AT knockdown results in dose-dependent AT lowering when fitusiran is given weekly or monthly subcutaneously. In clinical trials, fitusiran dose escalation has resulted in improved thrombin generation and clinical hemostasis as measured by reduction in annualized bleed rate. Unlike currently licensed drugs, this improvement was not only in patients with hemophilia A but in also those with hemophilia B, with or without inhibitors. In dental and surgical procedures, fitusiran also provided perioperative hemostasis in association with AT lowering. Fitusiran is well tolerated, with minor local injection site reactions, but in one subject with severe hemophilia A, the concomitant use of daily high-dose factor VIII, inconsistent with trial guidance to avoid high, repeat doses of clotting factor, was associated with fatal thrombosis, suggesting the need for caution when using hemostatic agents in conjunction with fitusiran. Preclinical in vitro and in silico studies indicate improvement in thrombin generation in rare bleeding disorder plasmas, including in plasmas from patients with severe factors V, VII, and X deficiency, suggesting potential therapeutic benefit.
Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the ...disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 × 1011vector genomes (vg)/kg to 1.8 × 1012vg/kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Pre-existing high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals.
Although liver transplantation (LTx) in HIV‐positive patients receiving highly active antiretroviral therapy (HAART) has been successful, some have reported poorer outcomes in patients coinfected ...with hepatitis C virus (HCV). Here we discuss the impact of recurrent HCV on 27 HIV‐positive patients who underwent LTx. HIV infection was well controlled posttransplantation. Survival in HIV‐positive/HCV‐positive patients was shorter compared to a cohort of HIV‐negative/HCV‐positive patients matched in age, model for end‐stage liver disease (MELD) score, and time of transplant, with cumulative 1‐, 3‐ and 5‐year patient survival of 66.7%, 55.6% and 33.3% versus 75.7%, 71.6% and 71.6%, respectively, although not significantly (p = 0.07), and there was a higher likelihood of developing cirrhosis or dying from an HCV‐related complication in coinfected subjects (RR = 2.6, 95%CI, 1.06–6.35; p = 0.03). Risk factors for poor survival included African‐American race (p = 0.02), MELD score >20 (p = 0.05), HAART intolerance postLTx (p = 0.01), and postLTx HCV RNA >30 000 000 IU/mL (p = 0.00). Recurrent HCV in 18 patients was associated with eight deaths, including three from fibrosing cholestatic hepatitis. Among surviving coinfected recipients, five are alive at least 3 years after LTx, and of 15 patients treated with interferon‐α/ribavirin, six (40%) are HCV RNA negative, including four with sustained virological response. Hepatitis C is a major cause of graft loss and patient mortality in coinfected patients undergoing LTx.
Recurrent Hepatitis C is a major source of morbidity and mortality in coinfected, HIV+/HCV+ patients undergoing liver transplantation.
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