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IntroductionThe TYSABRI Observational Program (TOP) is an ongoing observational study of natalizumab treatment in relapsing-remitting multiple sclerosis (RRMS) patients. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) was analysed in TOP UK (n=134) and global (N=6321) cohorts using data from July 2007 to November 2022. Cumulative probabilities of 24-week confirmed disability worsening (CDW) and improvement (CDI) were analysed in each cohort.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.15 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.18 (P<0.0001). ARR in subgroups based on number of prior disease modifying therapies and baseline Expanded Disability Status Scale scores will be presented. At 10 years follow-up, cumulative probability of CDI was 46.3% and 35.2% in the UK and global cohorts, respectively; cumulative probability of CDW was 60.3% and 40.7%.ConclusionsThe reduction in ARR on natalizumab was similar in the TOP UK and global cohorts, with the cumulative probability of CDI and CDW higher in the UK cohort. These findings support the real-world effectiveness of natalizumab.Support: Funded by Biogen. Disclosures: Included on the poster.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the ‘NEST-UK’ consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3–10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the ‘Core assessment program for intracerebral transplantations-HD’ assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Background Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2–4 consecutive days no later than 7 days from baseline. It will continue 4–5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2–3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.

IntroductionThe TYSABRI Observational Program (TOP) is an ongoing observational study of natalizumab treatment in relapsing-remitting multiple sclerosis (RRMS) patients. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) was analysed in TOP UK (n=134) and global (N=6321) cohorts using data from July 2007 to November 2021. A subgroup analysis assessed ARR in patients with one prior disease modifying therapy (DMT) in the UK (n=64) and global (n=2757) cohorts. Cumulative probabilities of 24-week confirmed disability worsening and improvement will be presented subsequently.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.15 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.18 (P<0.0001). In patients with one prior DMT, ARR decreased in UK patients from 2.13 in the year before initiation to 0.15 on natalizumab (P<0.0001), similar to the global decrease from 2.03 to 0.16 (P<0.0001).ConclusionsThe reduction in ARR on natalizumab was similar in the TOP UK and global cohorts, including in the subset of patients with one prior DMT. These findings support the real-world effectiveness of natalizumab.SupportBiogen. Disclosures on poster.

IntroductionThe TYSABRI Observational Program (TOP) is a large, ongoing observational study in relapsing- remitting multiple sclerosis (RRMS) patients treated with natalizumab. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) and cumulative probability of 24-week confirmed disability worsening (CDW; increase in Expanded Disability Status Scale [EDSS] score ≥1.5 from a baseline of 0.0,≥1.0 from a baseline between 1.0–5.5, or ≥0.5 from a baseline of ≥6.0) and improvement (CDI; decrease≥1.0 from a baseline EDSS score ≥2.0) were analysed in TOP UK (n=134) and global (N=6295) cohorts using data from July 2007 to November 2018. Updated data (as of November 2019) will be presented.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.19 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.21 (P<0.0001). At 7 years, probabilities of CDW and CDI were, respectively, 26.2% and 35.3% in UK patients and 27.9% and 32.1% globally.ConclusionsThese TOP UK results show disease control that is generally consistent with global TOP results, supporting natalizumab’s long-term effectiveness in real-world settings.SupportBiogen. Disclosures: Included on the poster.richard.nicholas@btinternet.com

IntroductionThe TYSABRI Observational Program (TOP) is an ongoing observational study of natalizumab treatment in relapsing-remitting multiple sclerosis (RRMS) patients. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) was analysed in TOP UK (n=134) and global (N=6320) cohorts using data from July 2007 to November 2020. A subgroup analysis assessed ARR in patients with one prior disease modifying therapy (DMT) in the UK (n=64) and global (n=2795) cohorts. Cumulative probabilities of 24-week confirmed disability worsening and improvement will be presented.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.16 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.18 (P<0.0001). In patients with one prior DMT, ARR decreased in UK patients from 2.13 in the year before initiation to 0.15 on natalizumab (P<0.0001), similar to the global decrease from 2.03 to 0.16 (P<0.0001).ConclusionsThe reduction in ARR on natalizumab was similar in the TOP UK and global cohorts, including in the subset of patients with one prior DMT. These findings support the real-world effectiveness of natalizumab.Support.Biogen. Disclosures: Included on the poster. jean.vonsy@biogen.com

Cervical dystonia (CD) involves painful involuntary contraction of the neck and shoulder muscles and abnormal posture in middle-aged adults. Botulinum neurotoxin type A (BoNT-A) is effective in treating CD but little is known about its associated cost-effectiveness. To evaluate the cost-effectiveness of abobotulinumtoxinA for treating CD from the UK payer perspective. A Markov model was developed to evaluate the cost-effectiveness of abobotulinum-toxinA versus best supportive care (BSC) in CD, with a lifetime horizon and health states for response, nonresponse, secondary nonresponse, and BSC in patients with CD (mean age: 53 years; 37% male). Clinical improvement measured using Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was mapped to utility using data from a randomized trial of abobotulinumtoxinA. Health care resource use, costs, and other inputs were from the British National Formulary, Personal Social Services Research Unit, published literature, or expert opinion. Costs and outcomes were discounted at 3.5% per annum. In the base case, the incremental lifetime quality-adjusted life-years (QALYs) gained from abobotulinumtoxinA arm versus BSC was 0.253 per patient, whereas the incremental cost was £7,160, leading to an incremental cost-effectiveness ratio (ICER) of £30,468 per QALY. One-way sensitivity analyses showed that these results were sensitive to the proportion of responders to abobotulinumtoxinA at first injection, duration between injections, the number of reinjections allowed among primary nonresponders, and any difference in baseline TWSTRS value between the BSC and abobotulinumtoxinA arms. Probabilistic sensitivity analysis showed that abobotulinumtoxinA was cost-effective 46% and 49% of times at thresholds of £20,000 and £30,000 per QALY, respectively. Scenarios are considered including vial-sharing, productivity losses, secondary response/nonresponse at subsequent injections, 5-year time horizon, and alternative reinjection intervals for BoNT-As produced ICERs ranging from cost-saving to £40,777 per QALY, versus BSC. AbobotulinumtoxinA was found to be cost-effective in treating adults with CD, at acceptable willingness-to-pay thresholds in the UK.

A 60 year old man with previous history of NHL (Non Hodgkin Lymphoma) presented with progressive dysphagia and dysarthria over two weeks.He had bilateral lower motor neuron facial weakness, diplopia on lateral gaze and nystagmus on examination. Working diagnosis was Miller Fisher syndrome and he was commenced on intravenous immunoglobulins. Subsequently he developed shortness of breath due to inability to maintain airway secondary to bulbar dysfunction. Review of MRI brain revealed enhancement of basal meninges with contrast suggestive of entrapment of cranial nerves. CSF showed 760 lymphocytes and elevated protein at 1.2 g/L. Immunophenotyping revealed the lymphocytes to be of Natural Killer (NK) cell origin leading to diagnosis of relapse of lymphoma involving CNS. He was diagnosed ten months ago with extranodal nasal NK/T cell lymphoma involving paranasal sinuses which is a rare subtype of NHL and is associated with Epstein-Barr virus. He was treated with four cycles of SMILE chemotherapy and local radiotherapy and had achieved complete remission as evidenced by a negative PET CT scan three months ago. This case stresses the importance of considering CNS relapse as a differential in patients presenting with neurological symptoms and history of lymphoma even though CNS relapse is rare for NHL (2.8%).

Background Despite the large and growing global burden of neurodegenerative diseases, it is not currently possible to detect neurodegeneration before irreversible damage to the brain occurs, as this is the point at which clinical symptoms manifest. There is, therefore, an unmet need for a reliable and accurate clinical test that is capable of detecting neurodegeneration before the brain suffers permanent damage. Our aim is to leverage epigenetic profiling technology to develop a sequencing‐based assay that can detect cell‐free DNA (cfDNA) originating from degenerating neuronal tissue in human plasma samples as a biomarker for neurodegeneration. Method Blood samples from a large cohort of neurodegenerative disease patients and from age‐ and sex‐matched controls are currently being collected. cfDNA will be directly sequenced using the Nanopore sequencing platform for native detection of cfDNA epigenetic modifications. A novel cell type deconvolution algorithm designed to handle to shortcomings of cfDNA sequencing data, Ranked Beta Binomial (RBB), will be used to detect neuron‐derived cfDNA fragments in plasma samples. Based on the results of cell type deconvolution we will assess the capability of this assay for detecting neurodegeneration using sensitivity and specificity analyses. Result RBB deconvolutes cell type proportions from both in silico cfDNA mixtures and spike‐in control cfDNA samples with known proportions of neuron‐derived cfDNA with high accuracy, even when the read depth of data and the proportions neuron‐derived cfDNA in the sample are both low. Furthermore, RBB is capable of detecting neuron‐derived cfDNA fractions with high accuracy when deconvoluting cell type proportions from cfDNA sequencing data derived from real human plasma samples. Conclusion While preliminary results for detection of neuron‐derived cfDNA as a biomarker neurodegeneration are promising, further development of cell type deconvolution methods and testing of diagnostic capability in patient populations are required in order to draw conclusions about the clinical utility of this assay.

Despite the large and growing global burden of neurodegenerative diseases, it is not currently possible to detect neurodegeneration before irreversible damage to the brain occurs, as this is the point at which clinical symptoms manifest. There is, therefore, an unmet need for a reliable and accurate clinical test that is capable of detecting neurodegeneration before the brain suffers permanent damage. Our aim is to leverage epigenetic profiling technology to develop a sequencing-based assay that can detect cell-free DNA (cfDNA) originating from degenerating neuronal tissue in human plasma samples as a biomarker for neurodegeneration. Blood samples from a large cohort of neurodegenerative disease patients and from age- and sex-matched controls are currently being collected. cfDNA will be directly sequenced using the Nanopore sequencing platform for native detection of cfDNA epigenetic modifications. A novel cell type deconvolution algorithm designed to handle to shortcomings of cfDNA sequencing data, Ranked Beta Binomial (RBB), will be used to detect neuron-derived cfDNA fragments in plasma samples. Based on the results of cell type deconvolution we will assess the capability of this assay for detecting neurodegeneration using sensitivity and specificity analyses. RBB deconvolutes cell type proportions from both in silico cfDNA mixtures and spike-in control cfDNA samples with known proportions of neuron-derived cfDNA with high accuracy, even when the read depth of data and the proportions neuron-derived cfDNA in the sample are both low. Furthermore, RBB is capable of detecting neuron-derived cfDNA fractions with high accuracy when deconvoluting cell type proportions from cfDNA sequencing data derived from real human plasma samples. While preliminary results for detection of neuron-derived cfDNA as a biomarker neurodegeneration are promising, further development of cell type deconvolution methods and testing of diagnostic capability in patient populations are required in order to draw conclusions about the clinical utility of this assay.