Alemtuzumab 30mg/1ml solution for infusion vials

BACKGROUND: Alemtuzumab (ALEM), an immune reconstitution therapy for multiple sclerosis (MS), has been associated with an increased risk of secondary autoimmune diseases, including Graves’ disease (GD). Graves’ orbitopathy following ALEM (GO-f-ALEM) is a rare, but relevant manifestation. GO-f-ALEM epidemiology and clinical course are still poorly characterized. MAIN BODY: The first aim of this paper was to perform a systematic review of published evidence of GO-f-ALEM in patients with MS, focusing on clinical features and management. Second aim was to integrate and compare literature data with real-world pharmacovigilance reports and institutional cases. A systematic review of published literature databases (PubMed, Embase, Scopus) from inception to December 2024 was performed according to PRISMA guidelines. A total of 42 published GO-f-ALEM cases in MS patients were identified. In parallel, as additional sources of data, which were not included in the systematic review analysis, 272 cases were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, and three institutional cases were described and analysed. GO-f-ALEM occurred more frequently in middle-aged adults (mean age 41 years old), with female predominance (60%) and a high rate of smoking (60%). GO generally occurred after 2–5 years from ALEM initiation. Fluctuating thyroid function and thyrotropin receptor antibody (TRAb) levels were commonly observed, with frequent need for definitive thyroid treatment (surgery or radioactive iodine - RAI). GO presentation was heterogeneous - from mild to sight-threatening forms - and mainly manifesting with lid retraction, proptosis, and diplopia. Concurrently, pharmacovigilance data from FAERS identified almost 300 reports of eye disorders potentially consistent with GO, thus suggesting under-diagnosis or under-reporting prevalence in literature. Institutional cases confirmed the potential for sight-threatening GO with dysthyroid optic neuropathy. CONCLUSIONS: Our data suggest that GO-f-ALEM is an underrecognized disorder within the spectrum of ALEM-induced autoimmunity, with peculiar features, as suggested by clinical and immunological observations and simultaneously by pharmacovigilance reports. Routine ophthalmic monitoring and standardized GO classification are essential for diagnosis and follow-up. Prospective studies are warranted to better define its epidemiology and guide optimised management strategies.

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ObjectiveTo comparatively evaluate the efficacy and safety of induction therapies in solid organ transplantation (SOT) using a Bayesian network meta-analysis (NMA).MethodsRandomized controlled trials (RCTs) assessing induction therapies were systematically identified across major databases (up to November 20, 2024). The screening, data extraction, and risk of bias (ROB) assessment were independently conducted by two reviewers through standardized tools. Bayesian NMA synthesized outcomes, including rejection, graft/overall survival, and infection rates.ResultsSixty-eight RCTs (9,626 patients) evaluating 12 therapies were included. Surface Under the Cumulative Ranking Area (SUCRA) probabilities identified alemtuzumab as the most effective agent for reducing rejection rates (93.9%), followed by antilymphocyte globulin (ALG, 87.0%) and belimumab (77.0%). For graft survival, OKT3 ranked highest (87.9%), with subsequent superiority for ALG (83.5%) and alemtuzumab (75.6%). Basiliximab demonstrated the highest overall survival benefit (88.0%), outperforming rabbit antithymocyte globulin (rATG, 82.1%) and inolimomab (70.3%). Belimumab showed the greatest infection risk reduction (94.4%), surpassing alemtuzumab (80.0%) and basiliximab (74.5%).ConclusionAlemtuzumab emerged as the optimal therapy for minimizing rejection, while OKT3 and basiliximab were superior for graft and overall survival, respectively. Belimumab exhibited the strongest potential for reducing incidence of infection. These findings highlight therapy-specific advantages for optimizing SOT outcomes.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/myprospero, identifier CRD42025634120.

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BackgroundEpidemiological research indicates a heightened incidence of cerebrovascular disorders among patients with multiple sclerosis (MS).ObjectivesThe aim of the present systematic review was to investigate the potential association between disease modifying therapies (DMTs) and the risk of stroke in MS patient populations.Data sources and methodsA systematic literature search was performed in MEDLINE and SCOPUS databases up to April 6, 2024, to identify randomized-controlled clinical trials (RCT), registry-based and cohort-studies, case-series, and case-reports reporting on acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) in MS patients under different DMTs.ResultsTwenty-one studies were included: 1 RCT, 6 registry-based or cohort studies, 2 case-series and 11 case-reports. Overall, DMTs appear to reduce the risk of stroke in MS patients, with DMT exposure linked to a 50% reduction of the risk of stroke compared to no DMT exposure. Although glatiramer acetate and dimethyl fumarate appear to lower the risk of stroke, concerns about fingolimod exists due to an observed elevated risk for ischemic heart disease and hypertension. Despite the absence of detected safety concerns with alemtuzumab at the MS population level, alemtuzumab-related complications, although rare, signal the need for heightened clinical vigilance. Similarly, β-interferons have been linked to life-threatening adverse events, comprising thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). No associations between the risk of stroke and other DMTs, comprising natalizumab and teriflunomide, were detected; yet, newly approved DMTs were underrepresented.ConclusionThese findings highlight the importance of personalizing DMT selection and monitoring cardiovascular risk factors to reduce stroke risk in patients with MS.Trial registrationPROSPERO CRD42024534470.

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BackgroundMultiple sclerosis is an immune-mediated inflammatory disease, causing long-term disability in young adults. Most cases begin as relapsing-remitting multiple sclerosis. Some people have a form of relapsing-remitting multiple sclerosis known as highly active relapsing-remitting multiple sclerosis, defined as multiple sclerosis with unchanged or increased disease activity despite prior treatment with at least one disease-modifying therapy.ObjectivesTo appraise the clinical and cost-effectiveness of natalizumab [Tysabri® (Biogen, Cambridge, MA, USA)] and natalizumab biosimilar [Tyruko® (Sandoz)] for treating highly active relapsing-remitting multiple sclerosis compared to other disease-modifying therapy.DesignSystematic review with network meta-analysis and economic model. Searches last updated in April 2024.ResultsWe included 42 studies (22,409 participants): 40 in people with relapsing-remitting multiple sclerosis and 2 in highly active relapsing-remitting multiple sclerosis. Six studies also reported data separately for highly active relapsing-remitting multiple sclerosis. Only four studies evaluated natalizumab or natalizumab biosimilar; none provided data on those with highly active relapsing-remitting multiple sclerosis. Follow-up ranged from 4 to 36 (median 24) months. Most interventions reduced relapses (39 studies, 17 interventions) and magnetic resonance imaging lesions (19 studies, 11 interventions for gadolinium enhancing lesions and 17 studies, 12 interventions for T2-weighted lesions) compared to placebo. Alemtuzumab, ocrelizumab, cladribine, natalizumab, fingolimod and peginterferon beta-1a reduced disease progression compared to placebo (15 studies, 12 interventions). There were no differences in any adverse events (24 studies, 16 interventions), serious adverse events (31 studies, 15 interventions) or treatment-related adverse events (8 studies, no network meta-analysis) for any intervention compared to placebo. Fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b and peginterferon beta-1a were associated with an increased treatment discontinuation (29 studies, 13 interventions). There was little evidence for a difference in quality of life. There was no evidence of a difference between natalizumab and natalizumab biosimilar for relapse rates [rate ratio 0.65 (95% credible interval 0.33 to 1.23], gadolinium enhancing lesions [hazard ratio 1.29 (0.69 to 2.37)], T2-weighted lesions [hazard ratio 1.07 (0.73 to 1.57)], any adverse events [hazard ratio 1.06 (0.77 to 1.46)] or treatment discontinuation [hazard ratio 0.48 (0.13 to 1.76)]. Data in highly active relapsing-remitting multiple sclerosis were available for fingolimod, ocrelizumab, alemtuzumab, cladribine, interferon beta, autologous haematopoietic stem cell treatment and placebo. We also included one study on natalizumab conducted in a population that was close to our definition of highly active relapsing-remitting multiple sclerosis. All interventions except interferon beta-1a were associated with reduced relapse risk compared to placebo (six studies; seven interventions). Compared with natalizumab-intravenous, natalizumab biosimilar-intravenous and natalizumab subcutaneous, all treatments had greater net benefit at £20,000-30,000/quality-adjusted life-year, with the only exception being ocrelizumab, which had lower net benefits. Costs were generally higher on natalizumab than other treatments, though there was no difference in quality-adjusted life-years with 95% credible interval completely overlapping. The results and conclusions were unchanged under all sensitivities. VOI analysis found that the greatest contributor to decision uncertainty was the effectiveness of treatments.ConclusionsThere is no direct evidence on the effectiveness of natalizumab or its biosimilar in patients with highly active relapsing-remitting multiple sclerosis. Limited data suggest similar effectiveness in patients with relapsing-remitting multiple sclerosis. The economic model found that natalizumab and natalizumab biosimilar were not cost-effective compared to any of the included comparators in highly active relapsing-remitting multiple sclerosis, with similar quality-adjusted life-years but higher costs, with the only exception being ocrelizumab.Future workThere is need for studies of natalizumab and natalizumab biosimilar in people with highly active relapsing-remitting multiple sclerosis.Study registrationThe study is registered as PROSPERO CRD42024556838.FundingThis award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR165943) and is published in full in Health Technology Assessment; Vol. 30, No. 60. See the NIHR Funding and Awards website for further award information.

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