To update the assessment of PML risk with natalizumab EID in comparison with Q4W dosing using TOUCH data as of June 30, 2023.

Background:Serum levels of neurofilament light chain (sNfL) are a potentially useful biomarker for assessing the efficacy of multiple sclerosis (MS) treatments. Objective:To compare levels of sNfL in patients with MS who switched from natalizumab every 4 weeks (Q4W) to extended interval dosing (EID) and patients who remained on Q4W dosing in real-world clinical practice. Methods:This was a retrospective analysis of samples from patients treated with natalizumab from 2010 to 2015 at a single center in the United States. Levels of sNfL were compared in patients who stayed on Q4W dosing or who switched to EID (parallel-arm analyses) and during Q4W and EID periods in patients who switched to EID (pre- and post-switch analyses). Results:The analysis included 139 patients (Q4W: n = 79; EID: n = 60). After adjustment, levels of sNfL did not significantly differ between patients who remained on Q4W dosing and those who switched to EID in parallel-arm analyses (adjusted Q4W-EID difference = 0.51 pg/mL; p = 0.60) or pre- and post-switch analyses (adjusted difference = 0.96 pg/mL; p = 0.10). Conclusion:These sNfL biomarker results suggest that the effectiveness of natalizumab is maintained in patients who switch from Q4W dosing to EID.

Objective: To update the assessment of PML risk with natalizumab EID in comparison with Q4W dosing using TOUCH data as of June 30, 2022. Background: Natalizumab treatment is associated with PML risk. Previous analyses of TOUCH data have demonstrated that natalizumab EID is associated with significantly lower PML risk than Q4W dosing in anti–JC virus (JCV) antibody-positive patients with multiple sclerosis. Design/Methods: TOUCH data were used to estimate PML risk for EID compared with Q4W dosing in anti-JCV antibody-positive patients using 3 pre specified analyses: primary (EID defined by the last 18 months of treatment), secondary (EID defined as any prolonged period of EID at any time during treatment), and tertiary (EID defined as a dosing history consisting primarily of EID). Hazard ratios (HRs) of PML with EID versus Q4W dosing were estimated using adjusted Cox regression models. Results: Compared with the previous analyses, patient numbers increased for all 3 analyses (EID: 9.9%–16.6%; Q4W: 2.2%–3.4%). For all analyses (EID vs Q4W), the mean number of natalizumab infusions (primary: 64.9 vs 56.4; secondary: 61.9 vs 39.8; tertiary: 41.9 vs 41.6), mean treatment duration (in months: primary, 74.5 vs 55.0; secondary, 68.3 vs 38.2; tertiary, 55.9 vs 41.2), and mean dosing interval (in days: primary, 36.5 vs 30.1; secondary, 35.4 vs 29.9; tertiary, 42.5 vs 30.8) were numerically greater with EID than Q4W dosing. All 3 analyses showed reduced risks of PML with EID vs Q4W (primary: 86% [HR=0.139 (95% confidence interval [CI], 0.066–0.294), P<0.0001]; secondary: 80% [HR=0.202 (0.113–0.361), P<0.0001]; tertiary: 96% [HR=0.040 (0.007–0.218)], P=0.0002). Conclusions: These results are consistent with all previous annual analyses of TOUCH patient data and demonstrate that natalizumab EID is associated with significantly lower PML risk than Q4W dosing. Continued follow-up will further quantify the amount of risk reduction with EID. Disclosure: Dr. Zhovtis Ryerson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Zhovtis Ryerson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Zhovtis Ryerson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Zhovtis Ryerson has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Zhovtis Ryerson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Zhovtis Ryerson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Zhovtis Ryerson has received research support from Biogen. The institution of Dr. Zhovtis Ryerson has received research support from Genentech. The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Octave. Dr. Foley has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics . The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon Therapeutics. The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. Dr. Foley has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Foley has stock in InterPRO Bioscience. The institution of Dr. Foley has received research support from Biogen. The institution of Dr. Foley has received research support from Novartis. The institution of Dr. Foley has received research support from Octave. The institution of Dr. Foley has received research support from Genentech. The institution of Dr. Foley has received research support from Imstem. The institution of Dr. Foley has received research support from Aegir. Dr. Kister has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech-Roche. The institution of Dr. Kister has received research support from Genentech. Dr. Kister has received publishing royalties from a publication relating to health care. Dr. Cutter has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Medimmune/Viela Bio, Medday, Merck/Serono, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Regeneron, Reckover Pharmaceuticals, Roche, TG Therapeutics.. Dr. Cutter has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Applied Therapeutics, AI therapeutics, AMO Pharma, Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics,Prothena Biosciences, Novartis, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc.. Dr. Cutter has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JASN. An immediate family member of Dr. Metzger has received personal compensation for serving as an employee of Ascendis. Dr. Metzger has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Interpro Bioscience. An immediate family member of Dr. Metzger has stock in Ascendis. An immediate family member of Dr. Metzger has stock in Biogen. An immediate family member of Dr. Metzger has stock in Rhythm. The institution of Judith Goldberg has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Amarin. The institution of Judith Goldberg has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Asieris. Judith Goldberg has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Statistical Science and Technology Associates, Inc.. Xiaochun Li has nothing to disclose. Dr. Riddle has received personal compensation for serving as an employee of Biogen. Dr. Riddle has received stock or an ownership interest from Biogen. Karen Smirnakis has received personal compensation for serving as an employee of Biogen. Karen Smirnakis has received stock or an ownership interest from Biogen. Dr. DSILVA has received stock or an ownership interest from BIOGEN. Mrs. Sinks has received personal compensation for serving as an employee of Biogen . Nolan Campbell has received personal compensation for serving as an employee of Biogen. Nolan Campbell has stock in Biogen. Tyler Lasky has received personal compensation for serving as an employee of Biogen. Tyler Lasky has stock in Biogen. Karthik Bodhinathan has nothing to disclose.

To describe patients who switched from anti-CD20 therapy to fumarates in the treatment of multiple sclerosis(MS)

Update the assessment of PML risk with natalizumab EID compared with every-4-week (Q4W) dosing using TOUCH data as of June 1, 2020.

L'analyse TOUCH 2017 montre un risque significativement plus faible de LEMP chez les patients avec une sérologie anticorps anti–JCV positive traités par natalizumab avec une extension de l'intervalle de dose (EID) par rapport à l'intervalle de dose standard (SID). Comparer les valeurs de l'index des anticorps anti-virus JC (JCV) chez les patients présentant une sérologie anti-JCV positive traités par natalizumab en EID versus SID dans l'analyse TOUCH 2017. Les valeurs de l'index obtenues chez les patients de l'analyse TOUCH désidentifiés et par Quest Diagnostics ont été appariées. Pour les patients ayant développé une LEMP, la valeur maximale de l'index > 6 mois avant le diagnostic de LEMP a été utilisée. Sinon, la valeur maximale globale de l'index a été utilisée. Dans chaque cohorte d'analyse, l'index des anticorps anti-JCV médian était plus élevé chez les patients EID versus SID (analyse primaire : 1,7 versus 1,3 ; analyse secondaire : 1,5 versus 1,4 ; analyse tertiaire : 1,6 versus 1,4). Des proportions plus importantes de patients EID versus SID présentaient des valeurs de l'index > 0,9 et > 1,5 dans les analyses primaire (70,2 % versus 61,1 % ; 55,0 % versus 45,9 % respectivement), secondaire (66,1 % versus 63,5 % ; 51,0 % versus 48,5 %) et tertiaire (70,5 % versus 63,2 % ; 53,9 % versus 48,4 %). Pour chaque analyse du risque de LEMP, les patients EID présentaient des valeurs de l'index des anticorps anti-JCV numériquement plus élevées que les patients SID. Le risque plus faible de LEMP avec l'EID versus SID n'est donc pas dû à l'index des anticorps anti-JCV plus faible chez les patients EID : l'EID est associé à un risque plus faible de LEMP versus SID.

Sunday, April 26April 14, 2020Free AccessSerum Neurofilament Light (sNfL) Levels in Patients with Relapsing-remitting Multiple Sclerosis (RRMS) Switching from Natalizumab Every-4-week (Q4W) Dosing to Extended Interval Dosing (EID) (2013)John Foley, Kuangan Xiong, Tammy Hoyt, Carol Singh, Evan Riddle, Carl de Moor, Nolan Campbell, and Tatiana PlavinaAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.2013 Letters to the Editor

Objective: Update the assessment of PML risk with natalizumab EID compared with Q4W dosing using TOUCH data as of June 1, 2019. Background: Natalizumab treatment is associated with PML risk. Previous analyses of patient data in the TOUCH database have demonstrated that EID is associated with lower risk of PML than Q4W dosing. Design/Methods: TOUCH data were used to determine whether EID is associated with lower PML risk compared with Q4W dosing in anti–JC virus antibody positive patients using 3 preplanned analyses specified for the 2017 study: a primary analysis (EID defined by the last 18 months of exposure), secondary analysis (EID defined as any prolonged period of EID in exposure history at any time), and tertiary analysis (EID defined as a dosing history consisting primarily of EID). Patients with average dosing intervals 12 weeks were excluded. Hazard ratios (HRs) of PML with EID and Q4W dosing were compared using adjusted Cox regression models and Kaplan-Meier estimates. Results: The updated analyses included more patients than the original 2017 study (primary: 2639 EID [32.7% increase] and 15,159 Q4W [15.4% increase]; secondary: 4237 EID [27.2% increase] and 17,493 Q4W [13.4% increase]; tertiary: 1048 EID [28.6% increase] and 26,540 Q4W [14.6% increase]). For all analyses, the mean number of natalizumab infusions and mean treatment duration were greater with EID than with Q4W dosing. Average dosing intervals were unchanged from 2017. The PML HR (95% confidence interval) was 0.11 (0.05–0.28; P Conclusions: This updated analysis of TOUCH patient data continues to demonstrate that natalizumab EID is associated with a significantly lower PML risk than Q4W dosing. Disclosure: Dr. Zhovtis Ryerson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Zhovtis Ryerson has received personal compensation for serving on speaker bureau for Biogen, Teva, Genentech and advisory board for Biogen and Celgene. Dr. Zhovtis Ryerson has received research support from Biogen. Dr. Foley has nothing to disclose. Dr. Chang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employees of and hold stock/stock options in Biogen. Dr. Chang holds stock and/or stock options in Biogen, stock greater than 10K which sponsored research in which Dr. Chang was involved as an investigator. Dr. Kister has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Has served on advisory boards of Biogen, Genentech.Dr. Cutter has received personal compensation from AMO Pharma, Argenix, Atara Bio-therapeutics, Axon, Biogen, BioLineRx, Bio-therapeutics, Brainstorm Cell Therapeutics, Charleston Laboratories, Inc., Click Therapeutics, Genentech, Genzyme, GW Pharma, Horizon Pharmaceuticals, Klein Buendel Inc., MedDay, MedImmune, Merck, Merck/Pfizer, Neurim, Novartis OPKO Biologics, Orphazyme, Pythagoras, Inc, Reata Pharmaceuticals, Receptos/ Celgene, Sanofi- Aventis, Roche, SciFluor, Somahlution, Teva Pharma-ceuticals, TG Therapeutics, UTHealth Houston Teva Neuroscience Dr. Metzger holds stock and/or stock options in Family member owns stock in Biogen which sponsored research in which Dr. Metzger was involved as an investigator. Dr. Goldberg has nothing to disclose. Dr. Li has nothing to disclose. Dr. Riddle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of and hold stock and/or stock options in Biogen. Dr. Riddle holds stock and/or stock options in Biogen which sponsored research in which Dr. Riddle was involved as an investigator. Dr. Smirnakis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of and hold stock and/or stock options in Biogen. Dr. Smirnakis holds stock and/or stock options in employee%20of%20and%20holds%20stock%2Fstock%20options%20in%20Biogen which sponsored research in which Dr. Smirnakis was involved as an investigator. Dr. Smirnakis holds stock and/or stock options in employee%20of%20and%20holds%20stock%2Fstock%20options%20in%20Biogen. Dr. Ren has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of and hold stock and/or stock options in Biogen. Dr. Hotermans has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Hotermans holds stock and/or stock options in Biogen which sponsored research in which Dr. Hotermans was involved as an investigator.Dr. Ho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Ho holds stock and/or stock options in Biogen.Dr. Campbell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Campbell has received compensation for serving on the Board of Directors of Received stock as employee of Biogen. Dr. Campbell holds stock and/or stock options in Biogen.

May 7, 2019April 9, 2019Free AccessReduced risk of progressive multifocal leukoencephalopathy (PML) associated with natalizumab extended interval dosing (EID): updated analysis of the TOUCH® Prescribing Program database (S26.006)Lana Zhovtis Ryerson, John Foley, Ih Chang, Ilya Kister, Gary Cutter, Ryan Metzger, Judith Goldberg, … Show All … , Xiaochun Li, Evan Riddle, Karen Smirnakis, Rachna Kasliwal, Zheng Ren, Christophe Hotermans, Pei-Ran Ho, and Nolan Campbell Show FewerAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.S26.006 Letters to the Editor

Objective To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). Methods This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. Results This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01–0.22, p < 0.001) and 0.12 (0.05–0.29, p < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. Conclusion Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. Classification of evidence This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

IntroductionNatalizumab, approved for 300 mg intravenous every-4-weeks dosing, is associated with PML risk. Prior studies have been inconclusive regarding EID’s impact on PML risk. The US REMS program (TOUCH) offers the largest data source that can inform on PML risk in patients on EID. This analysis aimed to determine whether natalizumab EID is associated with reduced PML risk compared with SID.MethodsInvestigators developed SID and EID definitions and finalised the statistical analysis plan while blinded to PML events. Average dosing intervals (ADIs) were ≥3 to<5 weeks for SID and >5 to≤12 weeks for EID. The primary analysis assessed ADI in the last 18 months of infusion history. The secondary analysis identified any prolonged period of EID at any time in the infusion history. The tertiary analysis assessed ADI over the full infusion history. Only anti-JC virus antibody positive (JCV Ab+) patients with dosing intervals≥3 to≤12 weeks were included. PML hazard ratios (HRs) were compared using adjusted Cox regression models and Kaplan-Meier estimates.ResultsAnalyses included 13,132 SID and 1988 EID patients (primary), 15,424 SID and 3331 EID patients (secondary), and 23,168 SID and 815 EID patients (tertiary). In primary analyses, ADI (days) was 30 for SID and 37 for EID; median exposure (months) was 44 for SID and 59 for EID. Most EID patients received >2 years SID prior to EID. The PML HR (95% CI) was 0.06 (0.01–0.22; p<0.001) for primary analysis and 0.12 (0.05–0.29; p<0.001) for secondary analysis (both in favour of EID); no EID PML cases were observed in tertiary analyses (Kaplan-Meier log-rank test p=0.02).ConclusionIn JCV Ab +patients, natalizumab EID is associated with a clinically and statistically significant reduction in PML risk as compared with SID. As TOUCH does not collect effectiveness data, further studies are needed.Study supportBiogen