Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

BACKGROUND: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015. OBJECTIVES: To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS. SEARCH METHODS: CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach. MAIN RESULTS: We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.

Utilization of peginterferon-ß-1a in the real-world practice for relapsing-remitting multiple sclerosis.

OBJECTIVE: Peginterferon ß-1a (PEG-IFN-ß-1a) is the most recent interferon beta formulation approved for treating relapsing-remitting multiple sclerosis (RRMS). We aim to describe the real-world utilization of PEG-IFN-ß-1a in RRMS and compare it with other injectable disease-modifying therapies (DMTs). PATIENTS AND METHODS: In this population-based study, we used 2015-2019 routinely collected healthcare data of the Campania region of Italy from National Healthcare System DMT prescriptions, inpatient and outpatient clinical records of hospitals in Campania, and the Federico II University MS clinical registry for a subset of patients. We included individuals with RRMS receiving new prescriptions of PEG-IFN-ß-1a [n=281; age = 38.8±12.3 years; females=70.5%; disease duration = 8.4±8.3 years; Expanded Disability Status Scale (EDSS) at baseline=2.0 (1.0-6.5)], glatiramer acetate [n=751; age = 46.0±11.4 years; females=67.1%; disease duration = 9.8±8.2 years; EDSS=4.0 (1.5-8.5)], and subcutaneous (SC) IFN-ß-1a [n=1,226; age = 39.7±11.7 years; females=66.5%; disease duration = 8.2±6.5 years; EDSS 2.5 (1.5-6.5)]. Adherence [medication possession ratio (MPR)], escalation to more effective DMTs, hospitalization rates and costs were measured. We used mixed-effect linear regression models (for adherence, hospitalization rates and costs) and Cox regression models (for escalation) to assess differences between PEG-IFN-ß-1a (statistical reference), glatiramer acetate, and SC IFN-ß-1a. All models included age, sex, previous treatment/untreated, year of treatment initiation, treatment duration, and adherence as covariates. RESULTS: Adherence was lower in glatiramer acetate (MPR = 0.91±0.1; Coeff=-0.11; p<0.01), and IFN-ß-1a (MPR = 0.92±0.1; Coeff=-0.08; p<0.01), compared with PEG-IFN-ß-1a (MPR = 1.01±0.1). The probability of escalating to more effective DMTs was higher for glatiramer acetate (14.9%; HR=4.09; p<0.01) and IFN-ß-1a (9.1%; HR=3.35; p=0.01), compared with PEG-IFN-ß-1a (4.9%). No differences in annualized hospitalization rates were identified between glatiramer acetate [annualized hospitalization rates (AHR) = 0.05±0.30; Coeff=0.02; p=0.31), IFN-ß-1a (AHR = 0.02±0.21; Coeff=0.01; p=0.97], and PEG-IFN-ß-1a (AHR = 0.02±0.24); however, monthly costs for MS admissions were higher for glatiramer acetate (€49.45±€195.27; Coeff=-29.89; p=0.03), compared with IFN-ß-1a (€29.42±€47.83; Coeff=6.79; p=0.61), and PEG-IFN-ß-1a (€23.91±€43.90). CONCLUSIONS: SC PEG-IFN-ß-1a and IFN-ß-1a were used in relatively similar populations, while glatiramer acetate was preferred in older and more disabled patients. PEG-IFN-ß-1a was associated with higher adherence and lower escalation rates toward more effective (and costly) DMTs.

The impact of metformin use on the outcomes of relapse-remitting multiple sclerosis patients receiving interferon beta 1a: an exploratory prospective phase II open-label randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disorder. Elevated levels of pro-inflammatory mediators and some oxidative stress parameters can accelerate the demyelination process. We aimed to investigate the efficacy and safety of metformin as an adjuvant therapy to interferon beta 1a (IFNß-1a) in relapsing-remitting multiple sclerosis (RRMS) patients. METHOD: Eighty RRMS patients were equally divided into 2 groups: the intervention group receiving IFNß-1a plus 2 gm of metformin once daily and the control group receiving IFNß-1a alone. Interleukin 17 (IL17), interleukin 22 (IL22), malondialdehyde (MDA), T2 lesions in magnetic resonance imaging (MRI) and expanded disability status scale (EDSS) were assessed at the baseline and then after 6 months. RESULTS: At baseline, there were no statistically significant differences between the two groups (p > 0.05). After 6 months, the change in the median (interquartile range) of the results for both the intervention and control group were; IL17 (- 1.39 (4.19) vs - 0.93 (5.48), p = 0.48), IL22 (- 0.14 (0.48) vs - 0.09 (0.6), p = 0.53), and EDSS (0 vs 0, p = 1), respectively. The mean (standard deviation) change in MDA for the intervention and control group was - 0.93 (2.2) vs - 0.5 (2.53), p = 0.038, respectively. For MRI results, 21 patients had stationary and regressive course and 1 patient had a progressive course in the intervention arm vs 12 patients had stationary and regressive course and 4 had a progressive course in the control arm, p = 0.14. CONCLUSION: Adding metformin to IFNß-1a demonstrated a potential effect on an oxidative stress marker (MDA). However, there is no statistically significant effect on immunological, MRI and clinical outcomes. We recommend larger scale studies to confirm or negate these findings. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT05298670, 28/3/2022.

Multiple sclerosis in Morocco: Epidemiological, clinical, and therapeutic profile.

OBJECTIVE: This study aims to describe the clinical, therapeutic, and epidemiological profiles of MS patients in Morocco. METHODS: This descriptive study involved 170 patients representing four Morocco regions. We collected the data using an electronic survey. RESULTS: The results show female dominance in patients with MS. Besides, most patients present with relapsing-remitting MS (RRMS). The main clinical symptoms reported by patients are fatigue, cognitive issues, spasticity, bowel or bladder complaints, and visual issues. Furthermore, the findings show that almost half of the patients use Interferon bêta-1a and azathioprine as disease-modifying therapies; 60.5 % use traditional and complementary medicine, of which 30.6 % use cupping, 30 % recite the Holy Quran, and 28.2 % use apitherapy. The findings show that there is a statistically significant relationship between specific MS factors such as professional activity (p = 0.0071), degree of satisfaction with treatment (p = 0.005), stress (p = 0.014), and the frequency of relapses. CONCLUSIONS: In addition to DMT, patients also use traditional and complementary medicine. There is also a relationship between some epidemiological characteristics and the frequency of relapses in patients with MS.

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 ß-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.

Development of IFNß-1a versions with reduced immunogenicity and full in vitro biological activity for the treatment of multiple sclerosis.

IFNß (recombinant interferon Beta) has been widely used for the treatment of Multiple sclerosis for the last four decades. Despite the human origin of the IFNß sequence, IFNß is immunogenic, and unwanted immune responses in IFNß-treated patients may compromise its efficacy and safety in the clinic. In this study, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of IFNß-1a. Two de-immunized versions of IFNß-1a were produced in CHO cells and designated as IFNß-1a(VAR1) and IFNß-1a(VAR2). First, the secondary and tertiary protein structures were analyzed by circular dichroism spectroscopy. Then, the variants were also tested for functionality. While IFNß-1a(VAR2) showed similar in vitro antiviral activity to the original protein, IFNß-1a(VAR1) exhibited 40% more biological potency. Finally, in vivo assays using HLA-DR transgenic mice revealed that the de-immunized variants showed a markedly reduced immunogenicity when compared to the originator.

Early use of high efficacy therapies in pediatric forms of relapsing-remitting multiple sclerosis: A real-life observational study.

BACKGROUND: Pediatric forms of multiple sclerosis are more active than those in adults. Yet, the effectiveness of different therapeutic approaches is not well studied in this population. Our objective was to compare the effectiveness of the early use of high efficacy therapies (HETs) with the effectiveness of moderate efficacy therapies (METs) in children with MS. METHODS: This observational study included patients diagnosed with pediatric MS, at 4 hospital centers in France, during a 10-year period. METs included: interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide; HETs included: fingolimod, natalizumab, ocrelizumab, alemtuzumab. The primary endpoint was the occurrence of a new relapse, the secondary endpoint was EDSS worsening. RESULTS: Sixty-four patients were included in the analysis (80% women; mean age 15.5 years, 81% treated with MET) with a median follow-up of 22.5 months. At baseline, 52 patients were on MET (interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide) and 12 patients were on HET (natalizumab, ocrelizumab). The cumulative probability of being relapse-free at 6.5 years was 23.3% on MET, vs 90.9% on HET (p = 0.013). The cumulative probability of no EDSS worsening did not differ between the 2 groups. CONCLUSION: Patients starting with METs had much higher clinical disease activity than those starting early with HETs. Rapid initiation of more aggressive treatment may allow better disease control; however, the data on EDSS worsening are not conclusive.

Assessing the duration of EDSS improvement after a therapy start: A novel approach applied to the long-term extension of the PRISMS study.

BACKGROUND: In a chronic and progressive disease such as multiple sclerosis (MS), the improvement on Expanded Disability Status Scale (EDSS) can be a transient event. Therefore, estimating the prevalence of disability improvement over time, accounting both for improvement incidence and duration, is of interest. The aim of this study was to show the application of a simple estimator for the proportion of patients with sustained improvement over time using data from the long-term extension of the PRISMS trial. METHODS: A total of 534 relapsing-remitting MS (RRMS) patients from the PRISMS trial were included. Patients with a baseline EDSS of 0 were excluded. Patients were randomized to placebo (n = 178), subcutaneous interferon beta-1a (sc IFN ß-1a) 22 µg (n = 181) or sc IFN ß-1a 44 µg (n = 175). At Year 2, patients receiving placebo were re-randomized to sc IFN ß-1a 22 µg or 44 µg (delayed sc IFN ß-1a) while patients receiving sc IFN ß-1a 22 µg or 44 µg continued their initial regimen. Patients were followed up for over 7 years post-randomization. Disability improvement was defined as a 1-point decrease in EDSS from baseline confirmed at 6 months. Prevalence of improvement was estimated as difference of Kaplan-Meier (KM) estimators while the cumulative incidence of improvement was calculated using the standard KM curves. RESULTS: No significant differences in cumulative incidence of EDSS improvement at 3 years between delayed sc IFN ß-1a (20.3%) and sc IFN ß-1a 22 µg (20.8%; p = 0.49) or 44 µg (21.3%; p = 0.33). When taking duration of improvement into account, the proportion of patients showing an improved condition after 3 years was 10.1% with delayed sc IFN ß-1a, 11.3% with sc IFN ß-1a 22 µg (p = 0.17) and 15.4% with sc IFN ß-1a 44 µg (p = 0.037) that was substantially maintained over the long term. CONCLUSIONS: With the use of this new statistical methodology, it is possible to estimate the time to improvement as well as the duration of improvement, information that is better suited to describing a non-final outcome like disability improvement. In this case, early sc IFN ß-1a 44 µg initiation had a greater proportion of patients with a sustained disability improvement over a long period of follow-up as compared to patients who had initially been randomized to placebo. In contrast, no significant differences on the cumulative incidence of improvement were observed.

Impact of interferon beta exposure on birth outcome and child development - Results from the post-authorisation safety study PRIMA.

BACKGROUND: Interferon beta therapies are well-established disease-modifying treatments for patients with relapsing multiple sclerosis (MS). Based on clinical evidence from two large cohort studies, both, the EMA and FDA updated the labels of the interferon beta class in terms of pregnancy and breastfeeding in 2019 and 2020, respectively. To complement pregnancy label updates with patient-reported real-world data, this study examined German pregnancy and outcome reports including available data on child development from women with MS treated with peginterferon beta-1a or intramuscular (IM) interferon beta-1a. METHODS: The post-authorisation safety study PRIMA included adult women diagnosed with relapsing-remitting MS or clinically isolated syndrome, who were treated with peginterferon beta-1a or IM interferon beta-1a before or during pregnancy and registered in the marketing authorisation holder's MS Service center patient support program. In the prospective part of the study, conducted from April to October 2021, data on developmental milestones of the newborns were collected via telephone interview from mothers reporting live births. RESULTS: In total, 426 women were enrolled, reporting 542 pregnancies that resulted in 466 live births. A total of 162 women completed the questionnaire for 192 live births (53.1% male). Newborns had Apgar scores indicative of healthy infants. Weight, length and head circumference at birth and physical growth curves up to 48 months lay within the expected range of the German general population. Most newborn screenings and examinations during check-ups were inconspicuous over the study period of 48 months. Out of 158 breastfed infants, 112 (70.9%) were breastfed exclusively until month 5. CONCLUSION: Study results confirmed former reports indicating that exposure to interferon beta therapies during pregnancy or lactation had no adverse effects on intrauterine growth and child development over the study period, which covered the first 4 years of life. These real-world data obtained within the scope of a patient support program for peginterferon beta-1a or IM interferon beta-1a corroborate German and Scandinavian registry data and support the label update of all interferon beta therapies. REGISTRATION: NCT04655222, EUPAS38347.

Interferon Beta-1a versus Glatiramer Acetate: Changes of Innate Immunity in a Group of Women with Multiple Sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations. METHODS: Sixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD). RESULTS: A statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10-20%. CONCLUSION: Innate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.

Assessment of adherence to, and persistence with, an electromechanical autoinjector for subcutaneous interferon beta-1a injections for multiple sclerosis treatment over 3 years.

BACKGROUND: Self-administration of subcutaneous interferon beta-1a (sc IFN ß-1a) can be achieved with the RebiSmart® electromechanical autoinjector. This study investigated adherence to, and duration of persistence with, the newest version of the device (v1.6) among 2644 people receiving sc IFN ß-1a for multiple sclerosis (MS). RESEARCH DESIGN AND METHODS: This retrospective, observational study utilized data from RebiSmart® devices, recorded on the MSdialog database, between January 2014 and November 2019. Adherence and persistence were evaluated over a 3-year period and assessed in relation to age, sex, injection type, and injection depth. RESULTS: The population of RebiSmart® users (N = 2644) comprised of 1826 (69.1%) females and mean age was 39 (range 16-83) years. Adherence to RebiSmart® use and data transfer to the MSdialog database was consistently high (mean 91.7%; range 86.8-92.6%), including across all variables (81.6-100%). Mean (±SD) persistence during the study period was 1.35 ± 1.06 years, with a maximum recorded persistence of 5.1 years. In multivariate analysis, the longest durations of persistence were observed among older individuals and males (p < 0.0001 and p = 0.0078, respectively). CONCLUSIONS: People living with MS were highly adherent to use of the RebiSmart® device, with higher persistence generally observed for older and/or male individuals.

It is important for people living with multiple sclerosis (MS) to take their medication regularly ­ and to keep doing so ­ in order to control their symptoms. Some people with MS receive a medication called interferon beta-1a (Rebif®) as a subcutaneous injection (given just under the skin), and the RebiSmart® electromechanical autoinjector was designed to help them to self-inject such medication. This study aimed to find out whether people were using the RebiSmart® device as often as they should be, and how long they continued to use it for. Information was taken from the MSdialog database, which recorded peoples' use of the RebiSmart® device between January 2014 and November 2019. Records for 2644 people using the device were analyzed. Results showed that the RebiSmart® device was used most of the time (around 91.7%). On average, people kept using the device for around a year and 4 months before stopping. This duration was generally longer for men compared with women, and longer for older people than younger people. These results increase our understanding of how people are using the RebiSmart® device to treat their MS symptoms.

Current and future trends in multiple sclerosis management: Near East perspective.

BACKGROUND: Multiple sclerosis (MS) prevalence is rising in the Middle East. Most MS medications are available in the region, but not all, possibly affecting neurologists' prescribing habits. OBJECTIVES: To provide an overview of the current practices of Near East (NE) healthcare practitioners by probing their prescribing decisions, to report the COVID-19 impacts on neurologists' prescribing habits, and to explore the future relevance of current medication used in MS management among other newcomers. METHODS: A cross-sectional study was carried out using an online survey from April 27, 2022, to July 5, 2022. The questionnaire was designed with the input of five neurologists representing five NE countries (Iran, Iraq, Lebanon, Jordan & Palestine). They identified several factors that play a crucial role in the optimal care of MS patients. The link was shared among neurologists using snowball sampling. RESULTS: The survey included 98 neurologists. Effectiveness and safety balance was the most important factor considered when selecting the MS treatment. Among patients with MS, the most challenging factor for the patients was thought to be related to family planning, followed by affordability and tolerability of side effects. In the treatment of mild to moderate relapsing remitting multiple sclerosis (RRMS) in men, Interferon beta 1a SC, Fingolimod, and Glatiramer acetate were the most commonly recommended treatments. Dimethyl fumarate substituted fingolimod in female patients. Interferon beta 1a SC was the safest treatment for mild to moderate RRMS. Interferon beta 1a SC was preferred over other treatments for patients with mild to moderate MS and planning for pregnancy (56.6%) or breastfeeding (60.2%). Fingolimod was not a choice for these patients. Neurologists seemed to discuss the top three treatments of Natalizumab, Ocrelizumab, and Cladribine with patients with highly active MS. When asked to position future disease-modifying therapies five years from today, more than 45% of physicians expressed a lack of information on Bruton's tyrosine kinase (BTK) inhibitors. CONCLUSIONS: Most neurologists in the NE region followed Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) recommendations for prescribing treatment. The treatment choice also depended on the availability of disease-modifying therapies (DMTs) in the region. Regarding the use of upcoming DMTs, there is a clear need for real-world data, long-term extension studies, and comparative studies to support their efficacy and safety profiles in treating patients with MS.

Quantitative comparison of the efficacy of clinical drug treatments for primary progressive multiple sclerosis.

OBJECTIVE: This study proposes a comprehensive quantitative evaluation of the efficacy of drugs and placebo in clinical trials for primary progressive multiple sclerosis (PPMS). METHODS: A literature search was conducted using the PubMed, EMBASE, and Cochrane library databases and the clinical studies reporting drug efficacy in the treatment of PPMS were included in the analyses. The cumulative proportion of patients without confirmed disability progression (wCDP%) was used as the main efficacy endpoint. The model-based meta-analysis method was used to describe the time course of each drug (as well as placebo) in order to rank the drug efficacy for the treatment of PPMS. RESULTS: Fifteen studies involving 3779 patients were included, of which, nine were placebo-controlled and six were single-arm trials. Twelve drugs were included in the study. The results showed that, except for biotin, interferon ß-1a, and interferon ß-1b, whose efficacy was comparable to the placebo, the efficacy of the other 9 drugs were significantly better than placebo. Among these, ocrelizumab showed outstanding performance, with wCDP% of 72.6 at 96 weeks, while the proportions of rest of the drugs ranged between approximately 55-70%. CONCLUSION: The results of this study provide the necessary quantitative information for both the rational clinical use of drugs and future clinical trials in primary progressive multiple sclerosis.

The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study.

BACKGROUND: White matter (WM) lesions and brain atrophy are present early in multiple sclerosis (MS). However, their spatio-temporal relationship remains unclear. METHODS: Yearly magnetic resonance images were analysed in 387 patients with a first clinical demyelinating event (FCDE) from the 5-year REFLEXION study. Patients received early (from baseline; N = 258; ET) or delayed treatment (from month-24; N = 129; DT) with subcutaneous interferon beta-1a. FSL-SIENA/VIENA were used to provide yearly percentage volume change of brain (PBVC) and ventricles (PVVC). Yearly total lesion volume change (TLVC) was determined by a semi-automated method. Using linear mixed models and voxel-wise analyses, we firstly investigated the overall relationship between TLVC and PBVC and between TLVC and PVVC in the same follow-up period. Analyses were then separately performed for: the untreated period of DT patients (first two years), the first year of treatment (year 1 for ET and year 3 for DT), and a period where patients had received at least 1 year of treatment (stable treatment; ET: years 2, 3, 4, and 5; DT: years 4 and 5). RESULTS: Whole brain: across the whole study period, lower TLVC was related to faster atrophy (PBVC: B = 0.046, SE = 0.013, p < 0.001; PVVC: B = -0.466, SE = 0.118, p < 0.001). Within the untreated period of DT patients, lower TLVC was related to faster atrophy (PBVC: B = 0.072, SE = 0.029, p = 0.013; PVVC: B = -0.917, SE = 0.306, p = 0.003). A similar relationship was found within the first year of treatment of ET patients (PBVC: B = 0.081, SE = 0.027, p = 0.003; PVVC: B = -1.08, SE = 0.284, p < 0.001), consistent with resolving oedema and pseudo-atrophy. Voxel-wise: overall, higher TLVC was related to faster ventricular enlargement. Lower TLVC was related to faster widespread atrophy in year 1 in both ET (first year of treatment) and DT (untreated) patients. In the second untreated year of DT patients and within the stable treatment period of ET patients (year 4), faster periventricular and occipital lobe atrophy was associated with higher TLVC. CONCLUSIONS: WM lesion changes and atrophy occurred simultaneously in early MS. Spatio-temporal correspondence of these two processes involved mostly the periventricular area. Within the first year of the study, in both treatment groups, faster atrophy was linked to lower lesion volume changes, consistent with higher shrinking and disappearing lesion activity. This might reflect the pseudo-atrophy phenomenon that is probably related to the therapy driven (only in ET patients, as they received treatment from baseline) and "natural" (both ET and DT patients entered the study after a FCDE) resolution of oedema. In an untreated period and later on during stable treatment, (real) atrophy was related to higher lesion volume changes, consistent with increased new and enlarging lesion activity.

Association of Higher Ocrelizumab Exposure With Reduced Disability Progression in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Ocrelizumab improved clinical and MRI measures of disease activity and progression in three phase 3 multiple sclerosis (MS) studies. Post hoc analyses demonstrated a correlation between the ocrelizumab serum concentration and the degree of blood B-cell depletion, and body weight was identified as the most influential covariate on ocrelizumab pharmacokinetics. The magnitude of ocrelizumab treatment benefit on disability progression was greater in lighter vs heavier patients. These observations suggest that higher ocrelizumab serum levels provide more complete B-cell depletion and a greater delay in disability progression. The current post hoc analyses assessed population exposure-efficacy/safety relationships of ocrelizumab in patients with relapsing and primary progressive MS. METHODS: Patients in OPERA I/II and ORATORIO were grouped in exposure quartiles based on their observed individual serum ocrelizumab level over the treatment period. Exposure-response relationships were analyzed for clinical efficacy (24-week confirmed disability progression (CDP), annualized relapse rate [ARR], and MRI outcomes) and adverse events. RESULTS: Ocrelizumab reduced new MRI lesion counts to nearly undetectable levels in patients with relapsing or primary progressive MS across all exposure subgroups, and reduced ARR in patients with relapsing MS to very low levels (0.13-0.18). A consistent trend of higher ocrelizumab exposure leading to lower rates of CDP was seen (0%-25% [lowest] to 75%-100% [highest] quartile hazard ratios and 95% confidence intervals; relapsing MS: 0.70 [0.41-1.19], 0.85 [0.52-1.39], 0.47 [0.25-0.87], and 0.34 [0.17-0.70] vs interferon ß-1a; primary progressive MS: 0.88 [0.59-1.30], 0.86 [0.60-1.25], 0.77 [0.52-1.14], and 0.55 [0.36-0.83] vs placebo). Infusion-related reactions, serious adverse events, and serious infections were similar across exposure subgroups. DISCUSSION: The almost complete reduction of ARR and MRI activity already evident in the lowest quartile, and across all ocrelizumab-exposure groups, suggests a ceiling effect. A consistent trend of higher ocrelizumab exposure leading to greater reduction in risk of CDP was observed, particularly in the relapsing MS trials, and was not associated with a higher rate of adverse events. Higher ocrelizumab exposure may provide improved control of disability progression by reducing disease activity below that detectable by ARR and MRI, and/or by attenuating other B-cell-related pathologies responsible for tissue damage. CLASSIFICATION OF EVIDENCE: This analysis provides Class III evidence that higher ocrelizumab serum levels are related to greater reduction in risk of disability progression in patients with multiple sclerosis. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in the open-label extension. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01247324 (OPERA I), NCT01412333 (OPERA II), and NCT01194570 (ORATORIO).

[Long-term Efficacy and Safety of Sampeginterferon-ß1a in the Treatment of Relapsing Remitting Multiple Sclerosis: a Randomized, Double-Blind Clinical Trial 104-Week Results]. / Dolgosrochnye dannye po effektivnosti i bezopasnosti preparata sampeginterferon-ß1a u patsientov s remittiruyushchim rasseyannym sklerozom: rezul'taty 104-nedel'nogo randomizirovannogo dvoinogo slepogo klinicheskogo issledovaniya.

OBJECTIVE: To assess the efficacy and safety of sampeginterferon-ß1a (samPEG-IFN-ß1a) 180 µg and 240 µg administered once every 2 weeks compared to placebo and low dose interferon beta-1a (LIB) 30 µg administered once weekly. MATERIAL AND METHODS: Patients with relapsing-remitting multiple sclerosis aged 18-60 years, with Expanded Disability Status Scale score ≤5.5 were randomized at a ratio of 2:2:2:1 to the following groups: samPEG-IFN-ß1a 180 µg, samPEG-IFN-ß1a 240 µg, LIB, placebo. After 20 weeks, the placebo group completed the study. After week 52, the final analysis was performed, which included the primary endpoint analysis, the LIB group patients completed their participation in the study. The patients in samPEG-IFN-ß1a groups continued to receive therapy with samPEG-IFN-ß1a 240 µg until week 100 inclusive. The results of the final analysis after 52 weeks have been previously published. The current article presents a long-term efficacy and safety of samPEG-IFN-ß1a after 104 weeks of the trial. RESULTS: The annualized relapse rate over the second year was 0.16 in the samPEG-IFN-ß1a 180 µg group and 0.09 in the samPEG-IFN-ß1a 240 µg group. By week 104, the proportion of relapse-free patients was 77.0% (87/113) and 83.3% (95/114) in the samPEG-IFN-ß1a 180 µg and 240 µg groups, respectively. There were no negative dynamics of MRI markers, neurological deficit parameters and cognitive functions by scales and tests. The safety profile of samPEG-IFN-ß1a was consistent with the known safety profile of IFN-ß therapy. CONCLUSION: Treatment with samPEG-IFN-ß1a is an effective and safe first-line therapy for relapsing-remitting multiple sclerosis patients.

Patient-reported outcomes are the strongest predictors of disease disability in intramuscular interferon ß-1a users.

Introduction: Patient-reported outcomes (PROs) are valuable measures for routine clinical care of people with multiple sclerosis (pwMS). Materials: 646 pwMS treated with interferon-ß-1a (IFN-ß-1a) were retrospectively included from the New York State Multiple Sclerosis Consortium. Clinical and PRO data at enrollment and 3 year follow-up were collected. PwMS with stable disease and disability worsening were matched (1:1) based on age, Expanded Disability Status Scale (EDSS) scores and disease duration. Disability worsening was determined based on trial criteria. Results: PwMS with future EDSS worsening had higher baseline and follow-up timed-25-foot walk (6.6 vs 5.5 s; 9.1 vs 5.5 s; p < 0.001) when compared with stable pwMS. Worsening pwMS reported higher baseline difficulties in getting up (odds ratio [OR] = 2.4; p = 0.009), climbing stairs (OR = 1.6; p = 0.024) and standing (OR = 2.2; p < 0.001). Worsening pwMS reported greater lower limb limitations (OR = 2.3; p = 0.004) and fatigue (OR = 1.8; p = 0.002). Conclusion: Higher fatigue and lower limb functional limitations are significant predictors of future disability worsening in pwMS.

A large retrospective study was carried out on people with multiple sclerosis (PwMS) being treated with intramuscular interferon-ß medication from the New York State Multiple Sclerosis Consortium. The aim of the study was to look at whether patient-reported and clinical measures could be used early on to predict whether PwMS have worsening of their disease. The study demonstrated that patient-reported levels of limitations in multiple physical and mental symptoms can predict future worsening in objectively quantified disability in PwMS who take intramuscular interferon-ß medication. Reported limitations in lower extremities and fatigue were the most predictive of future disability worsening.

Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon ß-1a.

OBJECTIVE: Evaluate the effect of subcutaneous interferon ß-1a (sc IFN ß-1a) versus placebo on the evolution of T1-weighted MRI lesions and central brain atrophy in in patients with a first clinical demyelinating event (FCDE). METHODS: Post hoc analysis of baseline-to-24 month MRI data from patients with an FCDE who received sc IFN ß-1a 44 µg once- (qw) or three-times-weekly (tiw), or placebo, in REFLEX. Patients were grouped according to treatment regimen or conversion to clinically definite MS (CDMS) status. The intensity of new lesions on unenhanced T1-weighted images was classified as T1 iso- or hypo-intense (black holes) and percentage ventricular volume change (PVVC) was assessed throughout the study. RESULTS: In patients not converting to CDMS, sc IFN ß-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P < 0.001 and P = 0.005) and new T1 iso-intense lesions (P < 0.001 and P = 0.002) after 24 months; only sc IFN ß-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P < 0.001). PVVC findings in patients treated with sc IFN ß-1a suggested pseudo-atrophy that was ~ fivefold greater versus placebo in the first year of treatment (placebo 1.11%; qw 4.28%; tiw 6.76%; P < 001); similar findings were apparent for non-converting patients. CONCLUSIONS: In patients with an FCDE, treatment with sc IFN ß-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

Treatment of Patients with Multiple Sclerosis Transitioning Between Relapsing and Progressive Disease.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating and neurodegenerative disease of the central nervous system with a wide variety of clinical phenotypes. In spite of the phenotypic classification of MS patients, current data provide evidence that diffuse neuroinflammation and neurodegeneration coexist in all MS forms, the latter gaining increasing clinical relevance in progressive phases. Given that the transition phase of relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS) is not well defined, and widely accepted criteria for SPMS are lacking, randomised controlled trials (RCTs) specifically designed for the transition phase have not been conducted. This review summarizes primary and secondary analyses and reports derived from phase III prospective clinical RCTs listed in PubMed of compounds authorised through the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of MS. The best data are available for interferon beta-1a (IFNb-1a) subcutaneous (s.c.), IFNb-1b s.c., mitoxantrone and siponimod, the latter being the most modern compound with likely the best risk-to-effect ratio. Moreover, there is a labels discrepancy for many disease-modifying treatments (DMTs) between the FDA and EMA, which have to be taken into consideration when opting for a specific DMT.

Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (III) A Randomized Trial with Interferon Beta-1a Products.

The US Food and Drug Administration (FDA) has taken steps to bring efficiency to the development of biosimilars, including establishing guidance for the use of pharmacokinetic and pharmacodynamic (PD) similarity study data without a comparative clinical study with efficacy end point(s). To better understand the potential role for PD biomarkers in biosimilar development and inform best practices for biomarker selection and analysis, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants. Eighty-four healthy participants (n = 12 per dose arm) received either placebo or one of three doses of either interferon ß-1a (7.5-30 µg) or pegylated interferon ß-1a (31.25-125 µg) to evaluate the maximum change from baseline and the baseline-adjusted area under the effect curve for the biomarkers neopterin in serum and myxovirus resistance protein 1 in blood. Both PD biomarkers increased following product administration with clear separation from baseline (neopterin: 3.4-fold and 3.9-fold increase for interferon ß-1a and pegylated interferon ß-1a, respectively; myxovirus resistance protein 1: 19.0-fold and 47.2-fold increase for interferon ß-1a and pegylated interferon ß-1a, respectively). The dose-response curves support that therapeutic doses were adequately sensitive to detect differences in both PD biomarkers for consideration in a PD similarity study design. Because baseline levels of both biomarkers are low compared with on-treatment values, there was little difference in using PD measures adjusted to baseline compared with the results without baseline adjustment. This study illustrates potential methodologies for evaluating PD biomarkers and an approach to address information gaps when limited information is publicly available for one or more PD biomarkers.