Cost-Effectiveness of Interferon Beta-1a, Interferon Beta-1b, and Glatiramer Acetate in Newly Diagnosed Non-primary Progressive Multiple Sclerosis

AbstractObjectiveTo perform a cost-effectiveness analysis of three immunomodulatory treatments for newly diagnosed nonprimary progressive MS: interferon beta-1a, interferon beta-1b, and glatiramer acetate.MethodsWe developed a state-transition model to estimate the health effects and costs associated with interferon beta-1a, interferon beta-1b, glatiramer acetate, and no treatment for hypothetical cohorts of men and women with non-primary progressive MS. We used the Expanded Disability Status Scale as the measure of disability and included both relapses and disease progression in the model. We evaluated treatment strategies assuming a 10-year treatment duration using the societal perspective. We elicited preferences for disability and treatment states using standard-gamble questions and modeled the disutility associated with treatment administration and side effects explicitly. Main outcome measures were net gains in quality-adjusted life expectancy and incremental cost-effectiveness ratios in dollars per quality-adjusted life year (QALY) gained.ResultsFor treatment duration of 10 years for newly diagnosed non-primary progressive MS, interferon beta-1a yielded the largest gain in quality-adjusted life expectancy with an incremental cost-effectiveness ratio of $2,200,000/QALY for women and$1,800,000/QALY for men, compared with no treatment. For a 5-year treatment duration, a “no treatment” strategy yielded more quality-adjusted life years than any of the treatment strategies. Cost-effectiveness ratios were similar for all three immunomodulatory treatments evaluated.ConclusionsCost-effectiveness results for all three immunomodulatory treatments for MS were unfavorable in the simulated study population under a wide range of assumptions. For treatment duration less than or equal to 5 years, expected benefits of treatment may not outweigh disutility associated with side effects and treatment discomfort

Dynamics of B-Cell Populations in CSF and Blood in Patients Treated with a Combination of Rituximab and Mitoxantrone.

Background. Mitoxantrone (MTX) and Rituximab (RTX) are successfully used for treatment of multiple sclerosis (MS) and can be combined to increase efficacy. Objective. We used MTX, RTX, and methylprednisolone in a single combined regiment and observed patients prospectively. Methods. We present results of observational pilot study of combined therapy of RTX and MTX in 28 patients with active MS. Therapeutic protocol consisted of two infusions within 14 days. First infusion was 1000 mg methylprednisolone (MP) IV, 1000 mg RTX IV, and 20 mg MTX IV. On day 14, 1000 mg MP IV and 1000 mg RTX IV were given. Patients were followed prospectively from 12 to 48 months. Results and Conclusion. There were no relapses among all 28 patients during the observation period. B-cell depletion of CD19+ and CD19+/CD27+ memory B-cell subpopulation in both compartments was confirmed in all patients at 6 months. We found a more rapid reconstitution of B cells in the CSF than in the peripheral blood and longstanding depression of CD19+CD27+ memory B-cell. Conclusion. Effectiveness of combined regimen of RTX and MTX could be related to longstanding depletion of CD19+CD27+ memory B-cell subset

Two-year results from a phase 2 extension study of oral amiselimod in relapsing multiple sclerosis.

BACKGROUND: Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis. OBJECTIVE: To assess safety and efficacy of amiselimod over 96 weeks. METHODS: After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results. RESULTS: Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: 'headache', 'lymphocyte count decreased', 'nasopharyngitis' and 'MS relapse' were most common (14.7%-16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12-lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug. CONCLUSION: For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity

Absorbing aerosols at high relative humidity: linking hygroscopic growth to optical properties

One of the major uncertainties in the understanding of Earth's climate system is the interaction between solar radiation and aerosols in the atmosphere. Aerosols exposed to high humidity will change their chemical, physical, and optical properties due to their increased water content. To model hydrated aerosols, atmospheric chemistry and climate models often use the volume weighted mixing rule to predict the complex refractive index (RI) of aerosols when they interact with high relative humidity, and, in general, assume homogeneous mixing. This study explores the validity of these assumptions. A humidified cavity ring down aerosol spectrometer (CRD-AS) and a tandem hygroscopic DMA (differential mobility analyzer) are used to measure the extinction coefficient and hygroscopic growth factors of humidified aerosols, respectively. The measurements are performed at 80% and 90%RH at wavelengths of 532 nm and 355 nm using size-selected aerosols with different degrees of absorption; from purely scattering to highly absorbing particles. The ratio of the humidified to the dry extinction coefficients (<i>f</i>RH<sub>ext</sub>(%RH, Dry)) is measured and compared to theoretical calculations based on Mie theory. Using the measured hygroscopic growth factors and assuming homogeneous mixing, the expected RIs using the volume weighted mixing rule are compared to the RIs derived from the extinction measurements. <br><br> We found a weak linear dependence or no dependence of <i>f</i>RH(%RH, Dry) with size for hydrated absorbing aerosols in contrast to the non-monotonically decreasing behavior with size for purely scattering aerosols. No discernible difference could be made between the two wavelengths used. Less than 7% differences were found between the real parts of the complex refractive indices derived and those calculated using the volume weighted mixing rule, and the imaginary parts had up to a 20% difference. However, for substances with growth factor less than 1.15 the volume weighted mixing rule assumption needs to be taken with caution as the imaginary part of the complex RI can be underestimated

Ozanimod in relapsing multiple sclerosis: Pooled safety results from the clinical development program

Esdeveniments adversos; Esclerosi múltiple; OzanimodEventos adversos; Esclerosis múltiple; OzanimodAdverse events; Multiple sclerosis; OzanimodBackground Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). In phase 3 trials, ozanimod was well tolerated and superior to interferon beta-1a 30 µg once-weekly in reducing clinical and radiologic disease activity. The objective of this integrated safety analysis was to evaluate the safety of extended ozanimod exposure in participants with RMS from all clinical trials and compare it with phase 3 trial data. Methods We report pooled incidence and study duration‒adjusted incidence rates (IR) of treatment-emergent adverse events (TEAEs) from an interim data cut (January 31, 2019) of RMS participants treated with ozanimod. Data were pooled from a phase 1 pharmacokinetic/pharmacodynamic trial, a placebo-controlled phase 2 trial with dose-blinded extension, 2 large active-controlled phase 3 trials, and an open-label extension (OLE). Results were compared with pooled phase 3 trial data. Results At the data cutoff, 2631 RMS participants had exposure to ozanimod 0.92 mg (mean 32.0 months) and 2787 had exposure to either ozanimod 0.46 or 0.92 mg (mean 37.1 months). The IRs per 1000 person-years (PY) for any TEAE (772.2) and serious TEAEs (33.2) in the overall population were similar to those in the phase 3 population (896.1 and 31.2, respectively). There were no serious opportunistic infections. There were no second-degree or higher atrioventricular blocks on electrocardiogram. Hepatic enzyme elevations declined over time. Malignancy rates remained low with longer exposure. Pulmonary function tests showed minimal reductions in lung function. Seven ozanimod-treated participants with comorbid risk factors had confirmed macular edema, including 3 in the ongoing OLE. Conclusions Safety results in this larger RMS population with greater ozanimod exposure demonstrated no new safety concerns and were consistent with phase 3 trial results

Ocrelizumab exposure in relapsing–remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension

Open-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing–remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound