Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study

The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.FUNDING: This study was supported by IDIVAL (NVAL 16/11)

Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

[EN] Background Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. Methods We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. Results We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. Conclusion MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.The authors thank the patients and healthy relatives for having participated in this project. We are grateful to the Eurobiobank CIBERER and the Biobank La Fe for their participation in the collection and processing of patient samples. We also thank the technicians at the Department of Genomics and Translational Genetics (CIPF) who participated in the quality control and processing of DNA samples (Virginia Rejas and Laura Ramírez), and the Bachelor¿s thesis student Andrea Ballester who helped with some clinical data collection. This project was funded by the Instituto de Salud Carlos III (ISCIII), FEDER (Grants no. PI12/00946 and PI16/00403 to TS, PI15/00187 to CE). MF holds a grant funded by the IIS La Fe (Grant no. 2015/0085). AS-M holds a grant funded by the Fundació Per Amor a l'Art (FPAA). JFV-C holds a ' Rio Hortega' contract funded by the ISCIII.Lupo, V.; Frasquet, M.; Sánchez-Monteagudo, A.; Pelayo-Negro, A.; García-Sobrino, T.; Sedano, MJ.; Pardo, J.... (2018). Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations. Journal of Medical Genetics. 55(12):814-823. https://doi.org/10.1136/jmedgenet-2018-105650814823551

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 reactivationFunding: This study received funding from IDIVAL (CSI 19/51 and CSI21/73). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publicatio