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  • 1
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    085 Clinical outcomes were better for relapsing-remitting multiple sclerosis (RRMS) patients who remained on natalizumab compared to those who switched to oral or injectable therapies after 2 years in the tysabri ® observational program (TOP)
    BMJ ; 2018
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 89, No. 6 ( 2018-06), p. A34.2-A34
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 89, No. 6 ( 2018-06), p. A34.2-A34
    Abstract: Natalizumab is a high-efficacy RRMS therapy. Data on post-natalizumab disease activity may be important for physician consideration. We compared outcomes in patients who switched to an oral or injectable therapy or remained on natalizumab and analysed post-natalizumab relapse predictors using data from TOP, an ongoing 10 year observational study of natalizumab-treated RRMS patients. Methods Data from November 2016 were analysed for patients who stayed on natalizumab (≥3 years natalizumab and only natalizumab during follow-up; n=2466; mean time on natalizumab: 5.5 years) or switched to oral (n=660) or injectable (n=95) therapies for ≥1 year after ≥2 years on natalizumab (mean post-natalizumab follow-up 2.5 vs 2.4 years). Annualised relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) worsening risks were evaluated. Disease activity predictors were compared using adjusted Cox models. Results Relapse risk was higher for oral switchers (hazard ratio [HR]=2.18; p 〈 0.001) or injectable switchers (HR=3.02; p 〈 0.001) than for patients who stayed on natalizumab 〉 2 years. EDSS worsening risk was similar for oral (HR=1.19; p=0.266) and higher for injectable (HR=2.52; p 〈 0.001) switchers compared with stayed-on-natalizumab patients. ARRs decreased after 2 years by 20.2% for stayed-on-natalizumab patients but increased from on-natalizumab rates by 17.8% in oral switchers (p 〈 0.001) and 108.1% in injectable switchers (p 〈 0.001). In oral switchers, lower relapse risk was predicted by shorter washout time ( 〉 12 weeks vs ≤4 weeks; HR=2.03; p 〈 0.001), fewer pre-natalizumab relapses (HR=1.24/relapse in the prior year; p 〈 0.001), lower baseline EDSS ( 〉 3.5 vs≤3.5; HR=1.44; p=0.007), and longer natalizumab duration ( 〉 3 years vs ≤3 years; HR=0.76; p=0.040). Conclusion Staying on natalizumab 〉 2 years yields better clinical outcomes than switching to oral or injectable therapies. For those discontinuing natalizumab, switching to an oral versus an injectable yields better outcomes. Disease activity risk in oral switchers is predicted by washout time, pre-natalizumab relapses and EDSS, and time on natalizumab. Study support Biogen.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2018-ANZAN.84
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2018
    detail.hit.zdb_id: 1480429-3
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  • 2
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    Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
    BMJ ; 2023
    In:  Gut Vol. 72, No. 2 ( 2023-02), p. 381-391
    Details
    In: Gut, BMJ, Vol. 72, No. 2 ( 2023-02), p. 381-391
    Abstract: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. Design Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case–control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). Results Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10 −9 , OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10 −5 , OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10 −44 ). Conclusion This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2022-327196
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1492637-4
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  • 3
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    116  Serum immunoglobulin levels and infection risk in Phase 3 ofatumumab trials in relapsing multiple sclerosis
    BMJ ; 2022
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 93, No. 6 ( 2022-06), p. A137.2-A137
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 93, No. 6 ( 2022-06), p. A137.2-A137
    Abstract: To assess the effect of ofatumumab vs teriflunomide on serum immunoglobulin (Ig) levels and evaluate potential association between decrease in IgM/IgG levels and infection risk. Methods Serum IgM/IgG levels were monitored at baseline (BL), W4, W12, and every 12 weeks thereafter. Proportion of patients with IgM/IgG levels below the lower limit of normal ( Results Mean IgM/IgG levels were within reference ranges over time. Over all post-BL visits, higher propor- tion of ofatumumab patients had IgM Conclusion Reduction in serum IgM levels was observed over time, Ig levels predominantly remained above LLN. No decrease in IgG levels was reported within the observation period. There was no apparent association between decreased Ig levels and infections in ofatumumab-treated patients. Funding statement This study was funded by Novartis Pharma AG, Basel, Switzerland. teresa.sawtell@novartis.com 83
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2022-ABN.441
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1480429-3
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  • 4
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    Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP)
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 6 ( 2020-06), p. 660-668
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 6 ( 2020-06), p. 660-668
    Abstract: The Tysabri Observational Programme (TOP), which began 〉 10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients. Methods These data provide a 10-year interim analysis of safety and effectiveness in TOP. Annualised relapse rates (ARRs) and disability progression/improvement were analysed using the Poisson model and the Kaplan-Meier method, respectively. Analyses included patients on natalizumab and those who discontinued natalizumab but remained in TOP. Results As of November 2017, TOP included 6148 patients. Overall, 829 patients (13.5%) experienced ≥1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had confirmed progressive multifocal leukoencephalopathy. SAE data were consistent with natalizumab’s known safety profile; no new safety signals were identified. A total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP. Median time on natalizumab was 3.3 (range 0–11.6) years; median follow-up time was 5.2 (range 0–10.8) years. The on-natalizumab ARR was 0.15, a 92.5% reduction from the year before initiation. Ten-year cumulative probabilities of disability worsening and improvement were 27.8% and 33.1%, respectively. On-natalizumab ARRs were similar between patients who discontinued or remained on natalizumab, suggesting limited attrition bias. Conclusions Since the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased. This 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab. Trial registration number NCT00493298 .
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-322326
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1480429-3
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  • 5
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    199 Changes in natalizumab exposure and PML incidence over time
    BMJ ; 2019
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 90, No. 12 ( 2019-12), p. e50.2-e50
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 90, No. 12 ( 2019-12), p. e50.2-e50
    Abstract: Since the identification in 2012 of three risk factors for natalizumab-associated progressive multifocal leukoencephalopathy (PML), changes in the PML incidence rate have been of interest. Methods The incidence of confirmed PML cases in Biogen’s postmarketing global safety database from November 2009 to November 2017 was evaluated retrospectively. Overall incidence in natalizumab-exposed patients was determined by the estimated total number of patients exposed and the number of confirmed cases. Changes in exposure patterns over time were evaluated by 12-infusion epochs. Results As of 30 November 2017, 180,656 patients worldwide had received ≥1 dose; overall natalizumab-associated PML incidence was 4.19/1000 patients. Since mid-2016, overall monthly incidence of PML appears to have stabilised, remaining between 4.18 and 4.24/1000. PML incidence was greatest in later, higher risk infusion epochs (≥37 infusions). The relative increase in the proportion of patients in higher-exposure epochs ( 〉 24 infusions) has declined from 2013 to 2017. Conclusions The stabilisation of overall natalizumab-associated PML incidence beginning mid-2016 coincides with the introduction of a new risk algorithm, suggesting that risk stratification factors are being incorporated into clinical practice and may continue to impact future incidence. Support: Biogen. Disclosures to be included on poster.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-ABN-2.168
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 1480429-3
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  • 6
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    RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours
    BMJ ; 2019
    In:  Gut Vol. 68, No. 7 ( 2019-07), p. 1287-1296
    Details
    In: Gut, BMJ, Vol. 68, No. 7 ( 2019-07), p. 1287-1296
    Abstract: We aimed at the identification of genetic alterations that may functionally substitute for CTNNB1 mutation in ß-catenin-activated hepatocellular adenomas (HCAs) and hepatocellular carcinoma (HCC). Design Large cohorts of HCA (n=185) and HCC (n=468) were classified using immunohistochemistry. The mutational status of the CTNNB1 gene was determined in ß-catenin-activated HCA (b-HCA) and HCC with at least moderate nuclear CTNNB1 accumulation. Ultra-deep sequencing was used to characterise CTNNB1 wild-type and ß-catenin-activated HCA and HCC. Expression profiling of HCA subtypes was performed. Results A roof plate-specific spondin 2 (RSPO2) gene rearrangement resulting from a 46.4 kb microdeletion on chromosome 8q23.1 was detected as a new morphomolecular driver of β-catenin-activated HCA. RSPO2 fusion positive HCA displayed upregulation of RSPO2 protein, nuclear accumulation of β-catenin and transcriptional activation of β-catenin-target genes indicating activation of Wingless-Type MMTV Integration Site Family (WNT) signalling. Architectural and cytological atypia as well as interstitial invasion indicated malignant transformation in one of the RSPO2 rearranged b-HCAs. The RSPO2 gene rearrangement was also observed in three β-catenin-activated HCCs developing in context of chronic liver disease. Mutations of the human telomerase reverse transcriptase promoter—known to drive malignant transformation of CTNNB1 -mutated HCA—seem to be dispensable for RSPO2 rearranged HCA and HCC. Conclusion The RSPO2 gene rearrangement leads to oncogenic activation of the WNT signalling pathway in HCA and HCC, represents an alternative mechanism for the development of b-HCA and may drive malignant transformation without additional TERT promoter mutation.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2018-317632
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 1492637-4
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  • 7
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    023  Relapse outcomes with natalizumab Q4W vs switch to Q6W
    BMJ ; 2022
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 93, No. 6 ( 2022-06), p. A20.3-A21
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 93, No. 6 ( 2022-06), p. A20.3-A21
    Abstract: The approved dosing of natalizumab (300 mg infusion every 4 weeks [Q4W]) is associated with risk of progressive multifocal leukoencephalopathy. This analysis from the TYSABRI Observational Program (TOP) compared relapse outcomes in patients who switched to natalizumab every 6 weeks (Q6W) after 1 year of Q4W with patients who remained on Q4W. Methods Eligible TOP patients had ≥1 year of natalizumab Q4W. Treatment duration-matched Q6W and Q4W patients (191 pairs) were compared by propensity score matching (PSM). Negative binomial model-estimated annualised relapse rate (ARR) and Kaplan-Meier-estimated relapse risk were compared during the post-switch and exposure-matched follow-up periods. Results After PSM, 135 pairs of Q6W and Q4W patients were included. Mean treatment duration was 4.4 years in both groups. There was no difference in ARR (Q6W: 0.231 [95% confidence interval (CI), 0.145–0.367]; Q4W: 0.254 [0.160–0.402] ; P=0.774) or relapse risk (hazard ratio [95% CI], 1.021 [0.583–1.789] ; P=0.940) between groups. Conclusions No significant difference in relapse outcomes was observed between patients who switched 4t6o Q6W and those who remained on Q4W. An ongoing randomized prospective trial of Q4W vs Q6W will inform further on the effectiveness of natalizumab Q6W. Support: Biogen. peiran.ho@biogen.com
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2022-ABN.62
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1480429-3
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