Safety and clinical effectiveness of peginterferon beta-1a for relapsing multiple sclerosis in a real-world setting: Final results from the Plegridy Observational Program.

Background: Interferon beta-1a remains an important treatment option for multiple sclerosis, particularly when safety or tolerability concerns may outweigh the benefits of higher-efficacy disease-modifying therapies. The five-year phase 4 Plegridy Observational Program (POP) study (NCT02230969) collected data on real-world safety and effectiveness of Plegridy® (peginterferon beta-1a) treatment in patients with relapsing multiple sclerosis. Objective: To explore the real-world safety and effectiveness of peginterferon beta-1a in patients with relapsing multiple sclerosis, including factors influencing treatment discontinuation. Methods: Data were collected prospectively from patients ≥ 18 years old with relapsing multiple sclerosis for overall population analysis and for subpopulations including newly/previously diagnosed patients, age, and experience with peginterferon beta-1a. Outcome measures included annualized relapse rates, adverse events, and predictors of time to treatment discontinuation. Results: Mean (SD) treatment duration in the overall population (N = 1172) was 896.0 (733.15) days. Incidence of adverse events was higher in new than experienced users (79.4% vs. 57.0%). New users were more likely than experienced users to discontinue (hazard ratio = 1.60; P < 0.0001). The adjusted annualized relapse rate was 0.09, and at the end of 5 years, 77.1% of patients were relapse-free. Conclusions: Peginterferon beta-1a is an effective therapy for managing relapsing multiple sclerosis. The identification of predictors of discontinuation can help inform strategies to enhance treatment persistence.

Analysis of Pregnancy Outcomes Following Exposure to Intramuscular Interferon Beta-1a: The AVONEX® Pregnancy Exposure Registry.

BACKGROUND AND OBJECTIVES: There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNß)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNß formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNß-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. METHODS: Pregnant women with multiple sclerosis exposed to IM IFNß-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8-12 weeks. Data were collected on IM IFNß-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. RESULTS: Three-hundred and two patients with a median (range) age of 31.0 (16-48) years and a median (range) gestational age at the time of enrollment of 10.1 (4-39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNß-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks' gestation (rate 10.5%; 95% confidence interval 7.2-15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8-10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNß-1a exposure. CONCLUSIONS: This large US registry study suggests IM IFNß-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNß-1a use during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00168714, 15 September, 2005.

Safety and clinical effectiveness of peginterferon beta-1a for relapsing multiple sclerosis in the real-world setting: Interim results from the Plegridy Observational Program.

BACKGROUND: The Plegridy Observational Program (POP) is an ongoing, 5-year, phase 4 real-world study of the safety and effectiveness of subcutaneous peginterferon beta-1a in patients with relapsing multiple sclerosis (RMS). METHODS: This interim analysis from POP assessed the safety and effectiveness of peginterferon beta-1a, including subgroup analyses of patients aged < 50 and ≥ 50 years, newly diagnosed and non-newly diagnosed patients, and new and experienced peginterferon beta-1a users. RESULTS: A total of 1208 patients enrolled in POP. Mean (standard deviation) peginterferon treatment duration in the overall population was 757.0 (529.5) days. The overall incidence of treatment-emergent adverse events (AEs) was 65.5%, and the incidence was higher in new than experienced peginterferon beta-1a users (78.1 vs 52.4%). The overall incidence of treatment-emergent serious AEs was 7.6%, and the incidence was lower in younger than older patients (5.8 vs 11.1%). No new or unexpected safety signals were reported. Overall treatment discontinuation due to AEs occurred in 20.7% of patients, with a higher proportion of new than experienced peginterferon beta-1a users (27.0 vs 14.2%) discontinuing treatment due to AEs. Flu-like symptoms and injection site reactions were significant predictors of time to treatment discontinuation. The adjusted annualized relapse rate (ARR) was 0.12 (95% confidence interval 0.11-0.13) in the overall population and was similar across all subgroups. In the overall population at 4 years, 79.1% of patients were relapse free, the estimated cumulative proportion of patients with confirmed disability worsening was 1.8%, and > 67% of patients achieved clinical no evidence of disease activity (NEDA). CONCLUSIONS: Safety data of patients enrolled in POP are consistent with the established clinical safety profile of peginterferon beta-1a. In addition, the low ARR and high proportion of patients achieving clinical NEDA at 4 years across all subgroups indicates the effectiveness of peginterferon beta-1a in treating RMS in real-world clinical settings.

Bioequivalence of intramuscular and subcutaneous peginterferon beta-1a: results of a phase I, open-label crossover study in healthy volunteers.

BACKGROUND: Peginterferon beta-1a administered every 2 weeks via subcutaneous (SC) injection is approved to treat adult patients with relapsing-remitting multiple sclerosis (RRMS) and relapsing forms of multiple sclerosis (RMS). However, associated injection site reactions (ISRs) can lead to treatment discontinuation. Prior studies with interferon beta-1a reported a lower frequency of ISRs with intramuscular (IM) administration than with SC administration. IM administration of peginterferon beta-1a may therefore represent a useful alternative treatment option. METHODS: A phase I, open-label, two-period crossover study randomized healthy volunteers to receive a single dose of peginterferon beta-1a 125 mcg administered IM followed by a single 125 mcg dose administered SC after a 28-day washout or vice versa. Blood samples were collected up to 504 h post dose to determine pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The primary endpoint was assessment of bioequivalence based on maximum serum concentration (Cmax) and area under the curve from time zero extrapolated to infinity (AUCinf). Other PK parameters, as well as PD (serum neopterin) and safety profiles, were also evaluated. RESULTS: The study enrolled 136 participants. Bioequivalence of IM and SC peginterferon beta-1a was established for both Cmax ([least squares (LS)] mean IM/SC ratio: 1.083 [90% confidence interval (CI), 0.975-1.203]) and AUCinf (LS mean IM/SC ratio: 1.089 [90% CI, 1.020-1.162]). Other PK and PD parameters were similar between administration routes, although moderate to high inter-subject variability was observed for IM and SC. Safety profiles were generally balanced between IM and SC administration. ISRs occurred at a lower frequency with IM [14.4% (95% CI, 8.89-21.56%)] than with SC [32.1% (95% CI, 24.29-40.70%)] administration (p = 0.0005). CONCLUSIONS: These results demonstrate bioequivalence between peginterferon beta-1a IM and SC and support the consideration of IM injection of peginterferon beta-1a as a viable treatment option in patients with RRMS and RMS.

Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low-dose-range of ionizing radiation.

Recent findings in populations exposed to ionizing radiation (IR) indicate dose-related lens opacification occurs at much lower doses (<2 Gy) than indicated in radiation protection guidelines. As a result, research efforts are now being directed towards identifying early predictors of lens degeneration resulting in cataractogenesis. In this study, Raman micro-spectroscopy was used to investigate the effects of varying doses of radiation, ranging from 0.01 Gy to 5 Gy, on human lens epithelial (HLE) cells which were chemically fixed 24 h post-irradiation. Raman spectra were acquired from the nucleus and cytoplasm of the HLE cells. Spectra were collected from points in a 3 × 3 grid pattern and then averaged. The raw spectra were preprocessed and principal component analysis followed by linear discriminant analysis was used to discriminate between dose and control for 0.25, 0.5, 2, and 5 Gy. Using leave-one-out cross-validation accuracies of greater than 74% were attained for each dose/control combination. The ultra-low doses 0.01 and 0.05 Gy were included in an analysis of band intensities for Raman bands found to be significant in the linear discrimination, and an induced repair model survival curve was fit to a band-difference-ratio plot of this data, suggesting HLE cells undergo a nonlinear response to low-doses of IR. A survival curve was also fit to clonogenic assay data done on the irradiated HLE cells, showing a similar nonlinear response.

Protective effect of melatonin against propoxur-induced oxidative stress and suppression of humoral immune response in rats.

Effect of melatonin in attenuation of propoxur induced oxidative stress and suppression of humoral immune response was studied in rats. Oral administration of propoxur (10 mg/kg) increased lipid peroxidation in serum after 28 days treatment. Superoxide dismutase, catalase and glutathione were also altered following propoxur exposure. In addition propoxur exposure markedly suppressed humoral immune response as assessed by antibody titre and plaque forming cell assay. Simultaneous treatment with melatonin (5 mg/kg, ip) markedly attenuated the effect of propoxur on (a) lipid peroxidation, (b) oxidative stress parameters and (c) immunotoxicity. Results have been discussed in the light of possible immunopotentiating and antioxidant effects of melatonin to understand the influence of oxidative stress on propoxur induced immunomodulation.