Long-lasting severe anemia following treatment with natalizumab for relapsing-remitting multiple sclerosis: a case report.

BACKGROUND: Natalizumab is a monoclonal antibody used to treat patients with relapsing-remitting multiple sclerosis. Anemia is a recognized side effect, but it is usually mild and of a short duration when natalizumab is stopped. Here, we describe a case of a young woman with severe and especially long lasting anemia associated with treatment with natalizumab, persisting up to a year after treatment was stopped. CASE PRESENTATION: A 24 year-old Caucasian woman with relapsing-remitting multiple sclerosis developed severe transfusion dependent anemia after 27 infusions with natalizumab, which was her first and only treatment for her multiple sclerosis. Extensive hematologic diagnostics did not reveal any malignant cause or any other plausible non-malignant cause for her anemia. The bone marrow was found to be hypercellular, with a maturation arrest of the erythropoiesis and with grade 1-2 fibrosis. No specific treatment for the anemia was given. The hemoglobin level showed signs of spontaneous increase after nearly one year after natalizumab was discontinued. CONCLUSION: Severe anemia can be caused by treatment with natalizumab. This case adds information to the few other similar reported cases, demonstrating the potential duration of the anemia, as well as detailed description of hematologic findings. The mechanism is most likely due to inhibition of α4 subunit of the α4ß1-integrin, which is present on both lymphocytes and erythroid precursor cells.

Switching from natalizumab to an anti-CD20 monoclonal antibody in relapsing remitting multiple sclerosis: A systematic review.

BACKGROUND: Use of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established. METHODS: In accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included. RESULTS: The overall incidence of clinical relapse during washout periods ranging from 4.4-10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02-0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %. CONCLUSIONS: This systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks.

The impact of social distancing measures on anti-JC virus serostatus changes before and during the COVID-19 pandemic in US patients with multiple sclerosis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic offered an epidemiological opportunity to evaluate if isolation and masking affected John Cunningham (JC) virus transmission. OBJECTIVE: This study aimed to assess the proportion of natalizumab-treated patients who converted to a positive anti-JCV antibody serostatus before and during the pandemic. METHODS: Data from TYSABRI Outreach: Unified Commitment to Health (TOUCH) for 22,375 US patients treated with natalizumab with anti-JCV antibody records were assessed in epochs annually from 2017 to 2022. RESULTS: Pre-pandemic anti-JCV antibody serostatus change was observed for 7.4%-7.7%. During the first and second years of the pandemic, 7.3% and 7.2% of patients' serostatus changed, respectively. CONCLUSION: The proportion of patients with anti-JCV antibody serostatus change did not significantly differ during the first 2 years of the pandemic compared with prior years. In contrast to seasonal influenza, masking and social distancing had no discernable effect on JCV serostatus change.

Imaging Very Late Antigen-4 on MOLT4 Leukemia Tumors with Cysteine Site-Specific 89Zr-Labeled Natalizumab Immuno-Positron Emission Tomography.

Very late antigen-4 (VLA4; CD49d) is a promising immune therapy target in treatment-resistant leukemia and multiple myeloma, and there is growing interest in repurposing the humanized monoclonal antibody (Ab), natalizumab, for this purpose. Positron emission tomography with radiolabeled Abs (immuno-PET) could facilitate this effort by providing information on natalizumab's in vivo pharmacokinetic and target delivery properties. In this study, we labeled natalizumab with 89Zr specifically on sulfhydryl moieties via maleimide-deferoxamine conjugation. High VLA4-expressing MOLT4 human T cell acute lymphoblastic leukemia cells showed specific 89Zr-natalizumab binding that was markedly blocked by excess Ab. In nude mice bearing MOLT4 tumors, 89Zr-natalizumab PET showed high-contrast tumor uptake at 7 days postinjection. Biodistribution studies confirmed that uptake was the highest in MOLT4 tumors (2.22 ± 0.41%ID/g) and the liver (2.33 ± 0.76%ID/g), followed by the spleen (1.51 ± 0.42%ID/g), while blood activity was lower at 1.12 ± 0.21%ID/g. VLA4-specific targeting in vivo was confirmed by a 58.1% suppression of tumor uptake (0.93 ± 0.15%ID/g) when excess Ab was injected 1 h earlier. In cultured MOLT4 cells, short-term 3 day exposure to the proteasome inhibitor bortezomib (BTZ) did not affect the α4 integrin level, but BTZ-resistant cells that survived the treatment showed increased α4 integrin expression. When the effects of BTZ treatment were tested in mice, there was no change of the α4 integrin level or 89Zr-natalizumab uptake in MOLT4 leukemia tumors, which underscores the complexity of tumor VLA4 regulation in vivo. In conclusion, 89Zr-natalizumab PET may be useful for noninvasive monitoring of tumor VLA4 and may assist in a more rational application of Ab-based therapies for hematologic malignancies.

Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis.

BACKGROUND: Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. OBJECTIVES: This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. METHODS: Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. RESULTS: We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. CONCLUSION: We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.

Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

Rates of John Cunningham virus seroconversion greatly reduced in natalizumab-treated patients during COVID-19-related lockdowns.

BACKGROUND AND PURPOSE: This study was undertaken to retrospectively compare rates of John Cunningham virus (JCV) seroconversion in natalizumab-treated patients before and during COVID-19-related community restrictions. Natalizumab is highly effective therapy for relapsing-remitting multiple sclerosis. Prolonged exposure to natalizumab in JCV-positive patients can cause progressive multifocal leukoencephalopathy, a potentially fatal brain infection. Serial assessment of JCV status is required for patients receiving natalizumab. METHODS: Patients receiving natalizumab at the Royal Melbourne Hospital were assessed for change in JCV serostatus and duration of exposure to natalizumab in two discrete time periods: from 1 February 2012 until 1 February 2017 ("pre-COVID"; n = 128) and from 1 April 2020 until 12 October 2022 ("COVID"; n = 214). A Poisson regression model adjusted for age at natalizumab commencement and sex was used to model seroconversion rate between the two time periods. RESULTS: The pre-COVID JCV seroconversion rate among natalizumab-treated patients at the Royal Melbourne Hospital was 9.08%. Conversely, we found a precipitous decline in JCV seroconversion during COVID lockdown. Annualized seroconversion during COVID-19-related restrictions was 2.01%. The annualized seroconversion rate was 4.7 times higher during the pre-COVID-19 period (95% confidence interval = 2.96-7.45, p < 0.0001) compared to the annualized seroconversion rate during COVID lockdown. Males had a 2× higher rate of seroconversion compared to females. CONCLUSIONS: JCV seroconversion among natalizumab-treated patients was markedly lower during COVID-19-related community restrictions. Restrictions observed in Melbourne were among the longest and most comprehensive implemented worldwide. This suggests the presence of modifiable risk factors that could lower rates of JCV seroconversion among natalizumab-treated patients.

Practical Clinical Guidelines for Natalizumab Treatment in Patients With Relapsing Multiple Sclerosis.

Natalizumab (TYSABRI®) was the first high-efficacy monoclonal antibody disease-modifying therapy (DMT) approved as a monotherapy for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. Because natalizumab is administered by intravenous infusion, infusion nurses play a key role in the care of natalizumab-treated patients. In the 16 years since approval, substantial data have been gathered on the long-term, real-world effectiveness and safety of natalizumab. This article provides a synopsis of this data, as well as practical information for optimizing patient care. This includes information on strategies to mitigate the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients, natalizumab use during pregnancy, and use with vaccines. It also includes guidance on the preparation and administration of natalizumab and monitoring of natalizumab-treated patients.

Serum Neurofilaments are a reliable biomarker to early detect PML in Multiple Sclerosis patients.

BACKGROUND: The earliest detection of progressive multifocal leukoencephalopathy (PML) is crucial in Natalizumab (NTZ)-treated Multiple Sclerosis (MS) patients. This study aims to assess serum Neurofilaments (sNFL) ability to early detect PML in longitudinal patients' follow-up. METHODS: NFL were retrospectively measured in four PML cases occurred at the Regional Referring Center for MS (CRESM, Italy), in samples collected since one year before PML diagnosis, at PML diagnosis, during PML and in post-PML follow-up. sNFL levels were interpreted according to previously defined reference values. Clinical examination and EDSS were performed at each NTZ infusion. Routinary MRI was undertaken every six months; after PML diagnosis, MRI was performed according to clinical evaluation. sNFL were also measured in 45 NTZ-treated patients experiencing NEDA-3 status for at least 12 months. RESULTS: Patients showed different PML onsets and manifestations: in 3 patients routinary brain MRI revealed radiological signs of PML preceding different clinical manifestations, while in one patient brain MRI was performed after the clinical onset. PML diagnosis was defined at the time of the first detection of JCV DNA in cerebrospinal fluid. The following different PML phases were considered: 1. Basal (up to 4 months before PML diagnosis): sNFL values were in the normal range in all patients' samples, except for one (median 9.1 pg/ml, range 6.2-15.1 pg/ml) 2. Pre-PML (within 3 months before PML diagnosis): sNFL were elevated in all available samples (median 19.50 pg/ml, range 15.50-33.80 pg/ml). 3. PML diagnosis: sNFL were elevated in all patients (median 59.20 pg/ml, range 11.1-101.50 pg/ml). 4. PML/IRIS: during this phase, sNFL levels reached their peak (median 96.35 pg/ml, range 20.5-272.9) in all patients. 5. Post-PML (recovery phase, starting from the first MRI without enhancement, up to the end of follow-up): sNFL levels showed a decrease (median 12.80 pg/ml, range 9.30-30.60); however, based on reference values, sNFL were still elevated in 2 out of 4 patients at the end of their follow-up (622 and 887 days after PML diagnosis). sNFL were always elevated when MRI scan suggested a suspicious of PML. In NEDA-3 patients, sNFL levels were in the normal range in all patients' samples (median 4.7 pg/ml, range 1.4-8.6 pg/ml). CONCLUSION: Elevated sNFL were observed not only at PML diagnosis, but also in pre-PML phase. At PML recovery, sNFL weren't normalized in all patients' samples, suggesting ongoing neuronal degeneration. sNFL represent a reliable biomarker and should be introduced in clinical practice as an additional/alternative parameter to MRI to early detect and monitor PML.

Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Radiological abnormalities in progressive multifocal leukoencephalopathy: Identifying typical and atypical imaging patterns for early diagnosis and differential considerations.

Progressive multifocal leukoencephalopathy (PML) is a rare viral central nervous system (CNS) demyelinating disease primarily associated with a compromised immune system. PML is seen mainly in individuals with human immunodeficiency virus, lymphoproliferative disease, and multiple sclerosis. Patients on immunomodulators, chemotherapy, and solid organ or bone marrow transplants are predisposed to PML. Recognition of various PML-associated typical and atypical imaging abnormalities is critical for early diagnosis and differentiating it from other conditions, especially in high-risk populations. Early PML recognition should expedite efforts at immune-system restoration, allowing for a favorable outcome. This review aims to provide a practical overview of radiological abnormalities in PML patients and address differential considerations.

Influence of physicians' risk perception on switching treatments between high- efficacy and non-high-efficacy disease­modifying therapies in multiple sclerosis.

BACKGROUND: The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians. OBJECTIVE: Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching. METHODS: Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021. RESULTS: Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%). CONCLUSIONS: Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs.

Liquid chromatography - tandem mass spectrometry method for determination of natalizumab in serum and cerebrospinal fluid of patients with multiple sclerosis.

Natalizumab is a humanized recombinant monoclonal IgG4 antibody used in the treatment of multiple sclerosis. Commonly used methods for natalizumab and anti-natalizumab antibodies quantification are enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, respectively. Measurement of therapeutic monoclonal antibodies can be challenging due to the resemblance to human plasma immunoglobulins. Recent developments in mass spectrometry enables to analyze vast variety of large protein molecules. The aim of this study was to develop a LC-MS/MS method for determining natalizumab in human serum and cerebrospinal fluid (CSF) and apply it to clinical settings. For successful quantification, it was necessary to find specific sequences of peptides in natalizumab. This immunoglobulin was treated with dithiothreitol and iodoacetamide, cleaved with trypsin into short specific peptides and determined on a UPLC-MS/MS system. An Acquity UPLC BEH C18 column at 55 °C and gradient elution was used for analysis. Intra- and interassay accuracies and precisions were tested at four concentration levels. Precision was determined by coefficients of variation and was in the range of 0.8-10.2 %, with accuracy in the range of 89.8-106.4 %. The concentration of natalizumab in patient samples ranged from 1.8 to 193.3 µg/mL. The method was validated according to the European Medicines Agency (EMA) guideline, met all acceptance criteria for accuracy and precision, and is suitable for clinical applications. In comparison to immunoassay, which can be elevated by cross-reaction with endogenous immunoglobulins, the results of developed LC-MS/MS method are more accurate and specific.

Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease.

Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the main cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA2/3 scores correlate with resistance to treatment and higher NRM. We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T-cell trafficking to the GI tract through the α4 subunit of α4ß7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA2/3 GVHD. Seventy-five patients who were evaluable were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events in >10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared with 150 well-matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and those treated with corticosteroids alone (60% vs 58%; P = .67% and 48% vs 48%; P = 1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival at 12 months in patients treated with natalizumab plus corticosteroids compared with controls treated with corticosteroids alone (38% vs 39%; P = .80% and 46% vs 54%; P = .48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high-risk GVHD. This trial was registered at www.clinicaltrials.gov as # NCT02133924.

Concomitant diagnosis of multiple sclerosis and human immunodeficiency virus (HIV) infection: case report and the review of literature.

BACKGROUND: To date, few cases of multiple sclerosis (MS) patients with concomitant Human Immunodeficiency Virus (HIV) infection have been described. However, none of the previously described cases has been treated with Natalizumab, probably due to the increasing risk of progressive multifocal leukoencephalopathy (PML). CASE: We report the case of a patient concomitantly diagnosed for HIV infection and MS treated with combined antiretroviral therapy (cART) and Natalizumab for 19 months, without clinical or radiological MS activity. CONCLUSIONS: Our case might suggest considering Natalizumab in patients with concomitant HIV infection, especially for those with significant disease activity requiring a high efficacy disease modifying treatment.

Switch to ocrelizumab in MS patients treated with natalizumab in extended interval dosing at high risk of PML: A 96-week follow-up pilot study.

We aimed to assess the long-term safety and effectiveness of ocrelizumab in a cohort of patients with multiple sclerosis (MS) at high risk of progressive multifocal leukoencephalopathy (PML), previously treated with natalizumab in extending interval dosing (EID), who switched to ocrelizumab and to compare them with patients who continued EID-natalizumab. Thirty MS patients previously treated with natalizumab in EID (every 8 weeks) were included in this observational retrospective cohort study. Among them, 17 patients were switched to ocrelizumab and 13 continued with EID-natalizumab. Except for the John Cunningham virus (JCV) index, no significant differences were detected between both groups. Main outcome measures included: annualized relapse rate (ARR), radiological activity, disability progression, and the NEDA-3 index. Patients were followed for 96 weeks. The median washout period in ocrelizumab-switchers was 6 weeks. Among them, AAR and radiological activity during follow-up were 0.03, without significant differences in comparison with the previous period on natalizumab-EID. The comparison between ocrelizumab-switchers and patients continuing on EID-natalizumab showed no significant differences in AAR, radiological activity, or disability progression. However, the proportion of patients maintaining a NEDA-3 status in week 96 was slightly superior among ocrelizumab-switchers (94 vs 69%). No serious adverse events were observed in any group. In conclusion, switching from EID-natalizumab to ocrelizumab can be considered as a therapeutic option, particularly in patients with MS at high risk of PML, to mitigate the risks of both PML and disease reactivation.

Peptide Mimotope-Enabled Quantification of Natalizumab Arm Exchange During Multiple Sclerosis Treatment.

BACKGROUND: Natalizumab, a therapeutic antibody used to treat multiple sclerosis, undergoes in vivo Fab arm exchange to form a monovalent bispecific antibody. Although highly efficacious, the immunosuppressive activity of natalizumab has been associated with JC polyomavirus-driven progressive multifocal leukoencephalopathy (PML). Development of assays that can distinguish between and quantify bivalent (unexchanged) and monovalent (exchanged) forms of natalizumab in clinical samples may be useful for optimizing extended interval dosing and reducing the risk of PML. METHODS: In vitro natalizumab arm exchange was conducted, along with peptide mimotope and anti-idiotype surface capture chemistry, to enable the development of enzyme-linked immunosorbent assays. RESULTS: An assay using a unique peptide Veritope TM was developed, which can exclusively bind to bivalent natalizumab. In combination with enzyme-linked immunosorbent assays that quantifies total natalizumab, the assay system allows quantification of both natalizumab forms. CONCLUSIONS: In this article, a novel assay for the quantification of unexchanged and exchanged natalizumab variants in clinical samples was developed. This assay will enable investigations into the clinical significance of the relationship of PK/PD with the monovalent-to-bivalent ratio, as it relates to the efficacy of the drug and risk of PML.