Neutralizing Antibody Status Research Articles

Comprehensive analysis and prediction of long-term durability of factor IX activity following etranacogene dezaparvovec gene therapy in the treatment of hemophilia B

Objective Congenital hemophilia B is a rare bleeding disorder caused by defects in the gene encoding factor IX (FIX) leading to coagulation deficiency. Recurrent bleeds may cause chronic pain, disability, and reduced quality of life. Phase 2 b and 3 single-arm, open-label, single-dose trials assessing etranacogene dezaparvovec gene therapy for hemophilia B have demonstrated sustained FIX activity levels over observed periods, but long-term durability of the treatment effect has not been established. Using statistical modeling, we estimate long-term durability of FIX activity levels after receiving etranacogene dezaparvovec. Methods Participants from Phase 2 b (N = 3; NCT03489291) and 3 studies (N = 52; NCT03569891) were included. Two participants who did not respond to treatment were excluded. FIX activity was assessed by one-stage activated partial thromboplastin time assay. FIX activity levels at Month 6 post-treatment were considered baseline. Bayesian and Frequentist linear mixed models predicted FIX activity levels up to 25.5 years at an individual and population level with pre-treatment adeno-associated virus 5 (AAV5) neutralizing antibody (NAb) status as primary covariate. Results Bayesian and Frequentist linear mixed models predicted no more than 6/55 (10.91%) observed participants would have FIX activity levels <2% up to 25.5 years post-infusion. Bayesian model-based predictions of future participants suggest >80% would be free from prophylactic FIX replacement products 25.5 years post-infusion. Both models predicted FIX activity levels were not significantly influenced by pre-treatment AAV5 NAb status. Conclusions People with hemophilia B receiving etranacogene dezaparvovec would likely achieve durable FIX activity levels and remain free of prophylactic FIX replacement products for up to 25.5 years following single administration. The long-term factor IX durability predictions are based on statistical methods and results in vivo may differ.

Neutralizing antibody response and associated factors in Coronavirus-19 disease (COVID-19) up to one month

Abstract Background There is a knowledge gap about the characteristics of neutralizing antibody (NAb) response in patients who recovered COVID-19. In this study, it is aimed to elucidate the factors affecting the presence and titers of antibodies up to 30-days after onset. Material and methods A total of 129 laboratory-confirmed COVID-19 patients were enrolled. Clinical data were obtained retrospectively. SARS-CoV-2 specific NAb, IgM, and IgG antibody responses were analyzed. Results SARS-CoV-2 specific NAb, IgM and IgG, were detected at the time of hospital discharge in 60.5%, 30.2%, and 51.9% of the patients, respectively. The median time for obtaining serum samples for antibody tests after symptoms’ onset was 11 days. The median titer of neutralizing antibody (SN50) was significantly higher in severe patients (25 vs. 7.5, p=0.009). Of the 23 severe patients, 52.2% (n=12) had higher NAb titers (i.e., SN50≥1:25) when compared to that in non-severe patients (OR=2.89; 95%CI=1.15–7.28, p=0.021), yet, the potential effect of follow-up time on NAb status and titers could not be ruled out. Conclusions The presence of antibody response is not the only determinative factor for recovery. The presence and higher titers of NAb were detected more in severe patients than their non-severe counterparts. Survival analysis suggested that this difference could at least be partially explained by the length of follow-up through antibody testing (at discharge) after symptoms’ onset.

The Safety of Agalsidase Alfa Enzyme Replacement Therapy in Canadian Patients with Fabry Disease Following Implementation of a Bioreactor Process.

Background and ObjectiveFabry disease, an X-linked lysosomal storage disorder characterized by absent or reduced alpha-galactosidase activity, is a lifelong disease that impairs patients’ quality of life. Patients with Fabry disease have a considerably shortened lifespan, with mortality being mainly due to renal failure, cardiovascular disease, or cerebrovascular disease. Enzyme replacement therapy with agalsidase alfa has been shown to attenuate the renal, cardiovascular, and neuropathic disease progression associated with Fabry disease. The objective of this study was to investigate the safety of a new animal component-free version of agalsidase alfa.MethodsA phase III/IV, open-label, single-arm, multicenter safety study was conducted in Canadian patients with Fabry disease between August 2011 and September 2017 as a regulatory requirement to assess the safety of agalsidase alfa produced using an animal component-free bioreactor process. Eligible patients had a documented diagnosis of Fabry disease and satisfied current Canadian guidelines for receiving enzyme replacement therapy for Fabry disease. Following treatment with animal component-free bioreactor-processed agalsidase alfa, treatment-emergent adverse events were monitored, and post hoc analyses of infusion-related reactions by antidrug antibody and neutralizing antibody statuses were conducted. The data were analyzed using descriptive statistics.ResultsA total of 167 patients (mean [standard deviation] age, 48.9 [14.8] years), including six pediatric patients (< 18 years of age), received at least one full or partial infusion of agalsidase alfa animal component-free. Fewer than 5% of treatment-emergent adverse events (212/4446) observed in 40 patients were reported as infusion-related reactions. Antidrug antibody and neutralizing antibody status did not affect the proportion of patients with infusion-related reactions. No clinically significant changes in vital signs were observed in patients over the course of the study.ConclusionsLong-term treatment with bioreactor-produced agalsidase alfa animal component-free did not reveal new safety signals in this population of Canadian patients with Fabry disease. The treatment-emergent adverse event profile was consistent with the clinical manifestations of the disease and the known safety profile of roller bottle-produced agalsidase alfa.Clinical Trial RegistrationClinicalTrials.gov identifier NCT01298141.

Serum Cotinine Does Not Predict Neutralizing Antibodies Against Interferon Beta in an Austrian MS Cohort.

Previous epidemiologic studies showed an increased risk of neutralizing antibody (NAb) development against Interferon beta in multiple sclerosis patients who smoke. Cotinine is an easily detectable metabolite of nicotine and, therefore, can be used as an objective surrogate marker for smoking status. We measured cotinine levels in NAb-positive and NAb-negative patients to find a potential association of nicotine consumption and NAb development. Cotinine was measured in 37 patients with known smoking status and in 123 patients with unknown smoking status, all of whom were routinely tested for NAb. Cotinine was detected by an enzyme-linked immunosorbent assay, inhibition assay. We compared cotinine levels by NAb status and tested for the strength of association between cotinine and NAb status. We found a discrepancy between smoking status stated by patients and status defined by cotinine levels in 7 of 37 patients. In both cohorts, together with and without previously known smoking status (n = 160), we found 34% and 39% smokers, respectively, as defined by cotinine levels in NAb-negative and NAb-positive patients (P = 0.511). In our analysis, smoking was not associated with higher risk of NAb development. Moreover, smoking habits stated by patients do not always correlate with cotinine levels.

Gender effects on treatment response to interferon-beta in multiple sclerosis.

Gender appears to play a role in incidence and disease course of multiple sclerosis (MS). The objective was to determine whether male and female patients with MS respond differently to interferon-beta treatment in terms of reduction in relapse rates. We included all 2033 patients with relapsing-remitting MS who started treatment with interferon-beta from 1996 to 2003, identified from the Danish Multiple Sclerosis Treatment Register. We defined neutralizing antibody (NAb)-positive and NAb-negative periods in the single patient by the results of the NAb tests. Patients served as their own controls, and relapse rates were compared between NAb-negative and NAb-positive periods. NAbs significantly abrogated the interferon-beta treatment efficacy in both genders. The all-over women:men relapse rate ratio irrespective of NAb status was 1.47 (95%CI; 1.28-1.68). In a generalized linear Poisson models analysis with relapse counts as response variable, the main effects NAbs, sex, age at treatment start and number of relapses in 2 years before treatment start were strongly significant, but the effect of NAbs on relapse rates did not differ significantly between men and women. As NAbs influenced the on-treatment relapse rates strongly in both sexes but without statistical significant difference, there is no indication of different effects of interferon-beta in men or women.

Neutralizing antibodies against interferon beta: fluctuation is modest and titre dependent

Neutralizing antibody (NAb) titres may vary over time and thereby some patients can either lose or regain therapeutic effect of interferon beta (IFNbeta). We assessed NAb titres in a large sample of multiple sclerosis (MS) patients to identify the pattern of fluctuation during 1-3 years. Data from IFNbeta-treated MS patients who had been tested for NAbs twice (n = 822) were analysed. NAb titres were compared between the first and the second samples across the critical NAb level of 150 TRU/ml, which we have previously reported to correlate with loss of bioactivity. Of patients with NAb titres high enough to indicate loss of bioactivity (>150 TRU/ml) in the first analysis 15% showed titres low enough to indicate a regained bioactivity. Conversely, 6% of those without detectable NAbs or NAb titres below the critical level of 150 TRU/ml had shifted to titres above this limit, indicating potential loss of bioactivity. Fluctuation did not differ between IFNbeta preparation used, treatment duration or sampling interval. A first NAb test is prognostic for the NAb status during the coming 1-3 years. Choice of IFNbeta preparation had no influence on the chance of reverting to lower levels once NAb titres are high.

Interferon β-1a in MS

Debate continues concerning the relevance of neutralizing antibody (NAb) development on the efficacy of interferon (IFN) therapy in patients with multiple sclerosis (MS). The PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study of subcutaneous IFNbeta-1a showed significant benefit on all efficacy outcomes with no significant impact from NAb development on relapses at 2 years. The 2-year extension permitted longer observation following NAb development. Exploratory post-hoc analyses of pharmacodynamic response and clinical and MRI outcomes were performed on data from 368 patients with relapsing MS treated with IFN from study start, based on NAb status. Persistent NAbs, above 20 NU/mL, were present in 14% of the 44-microg three times weekly (TIW) and 24% of the 22-microg TIW group over 4 years. NAb development was associated with reduced pharmacodynamic marker induction at 1 year. Over the entire 4 years of study, relapse and disability measures were similar between NAb+ and NAb- patients. However, once NAbs developed, significant differences were noted between NAb+ and NAb- groups, particularly on MRI and relapse measures. The presence of binding antibodies alone did not affect outcome. Neutralizing antibody development in interferon-treated patients is correlated with reduced efficacy and is a potential cause for renewed disease activity.