Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies

Ho, Pei-Ran; Koendgen, Harold; Campbell, Nolan; Haddock, Bill; Richman, Sandra; Chang, Ih

doi:10.1016/s1474-4422(17)30282-x

Cited by 248 publications

(239 citation statements)

References 20 publications

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“…However, natalizumab treatment has been associated with a risk of progressive multifocal leucoencephalopathy (PML), an opportunistic brain infection caused by reactivated John Cunningham virus . Three risk factors of developing natalizumab‐associated PML are known: the presence of anti‐John Cunningham virus antibodies, previous immunosuppression, and treatment duration, especially beyond 2 years …”

Section: Introductionmentioning

confidence: 99%

“…13 Three risk factors of developing natalizumab-associated PML are known: the presence of anti-John Cunningham virus antibodies, previous immunosuppression, and treatment duration, especially beyond 2 years. [14][15][16] AJM300 (INN; Carotegrast methyl) is a small-molecule α4-integrin antagonist that can be administered orally and is almost nonimmunogenic. An orally administered active drug would have the additional advantage of potentially increasing drug adherence.…”

Section: Introductionmentioning

confidence: 99%

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AJM300, a novel oral antagonist of α4‐integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects

Fukase

Kajioka

Oikawa

et al. 2020

Brit J Clinical Pharma

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Aims AJM300 is an oral antagonist of α4‐integrin that reduces inflammation by blocking leucocyte trafficking. This study aimed to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of AJM300 in healthy male subjects. Methods A total of 23 subjects were randomised to receive 240 mg (n = 6), 480 mg (n = 5), 960 mg (n = 6) of AJM300 or the corresponding placebo (n = 2 per group). The study drugs were taken orally 3 times daily after each meal on the first day followed by a 4‐day washout period. Thereafter, multiple‐dose administration was conducted for 6 consecutive days. The pharmacokinetic parameters of AJM300 and its active metabolite (HCA2969) were assessed, and total white blood cells and the differential cell count were used to determine the pharmacodynamic effects. Adverse events (AEs) were also monitored. Results The plasma AJM300 and HCA2969 concentration–time curves displayed a triphasic pattern on Day 1 (single‐day administration) and Day 10 (last day of multiple dosing), whereas the concentration of HCA2969 was much higher than that of AJM300. A significant but transient increase in lymphocyte count was observed after AJM300 dosing at all dosages tested compared with the placebo. The increase was sustained over a 24‐h period only at the 960‐mg dosage. In particular, a significant increase in the lymphocyte count compared to placebo (mean, 50.58%; 95% confidence intervals, 20.40–80.76) was observed at the first 960‐mg dose on Day 10. Six (26.1%) subjects reported ≥1 AEs, all of which were mild and resolved spontaneously. Conclusion The maximal and 24‐h sustained pharmacodynamic effects were demonstrated at the 960‐mg dosage after oral administration of AJM300 3 times daily for 6 days, which was also found to be safe and well tolerated.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AJM300, a novel oral antagonist of α4‐integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects

Fukase

Kajioka

Oikawa

et al. 2020

Brit J Clinical Pharma

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“…Recent data reveal an estimated annual risk of 10/1000 in year six of treatment in MS patients with an anti‐JCV index of >1.5 65. This risk is substantially higher than 0.01/1000 patients in patients with an index of ≤0.9 in year one.…”

Section: Discussionmentioning

confidence: 99%

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Hussain

Cravens

Doelger

et al. 2018

Ann Clin Transl Neurol

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ObjectiveNatalizumab blocks α4‐integrin‐mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α4‐integrin deficiency.MethodWe generated the conditional knock out mouse strain Mx1.Cre+ α4‐integrinfl/fl, in which the α4‐integrin gene is ablated upon treatment with the TLR3 agonist poly I:C. Adoptive transfer of purified lymphocytes from poly I:C‐treated Mx1.Cre+ α4‐integrinfl/fl donors into naive recipients recapitulates immunosuppression under natalizumab. Active experimental autoimmune encephalomyelitis (EAE) in Mx1.Cre+ α4‐integrinfl/fl mice treated with poly I:C represents immune‐reconstitution.ResultsAdoptive transfer of T cells from poly I:C treated Mx1.Cre+ α4‐integrinfl/fl mice causes minimal EAE. The in vitro migratory capability of CD45+ splenocytes from these mice is reduced. In contrast, actively‐induced EAE after poly I:C treatment results in full disease susceptibility of Mx1.Cre+ α4‐integrinfl/fl mice, and the number and composition of CNS leukocytes is similar to controls. Extravasation of Evans Blue indicates a compromised blood‐brain barrier. Poly I:C treatment results in a 2‐fold increase in IFN β transcription in the spinal cord.InterpretationOur data suggest that TLR3 agonism in the setting of relative α4‐integrin deficiency can reestablish CNS immune surveillance in an experimental model. This pathway may present a feasible treatment strategy to treat and prevent PML under natalizumab therapy and should be considered for further experimental evaluation in a controlled setting.

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“…3,24 Natalizumab Two global phase III clinical trials; that is, the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) 25 and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing-Remitting Multiple Sclerosis (SENTINEL) 26 studies, showed significant efficacy in reducing clinical relapse rates and risk of sustained progression of disability. 29 Overall, it is recommended to check the presence of anti-JC virus antibody before initiating natalizumab administration, and to thoroughly discuss the risk of natalizumab treatment with patients and their families. 27 Natalizumab was approved in March 2014 in Japan, almost 10 years after its approval in the USA.…”

Section: Fingolimodmentioning

confidence: 99%

Disease‐modifying drugs for multiple sclerosis in Japan: A focus on the 2017 Japanese guidelines and the 2018 supplement

Niino

Miyazaki

2019

Clinical & Exp Neuroim

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Currently, six disease-modifying drugs (DMD) for multiple sclerosis are available in Japan: subcutaneous interferon-b-1b, intramuscular interferon-b-1a, glatiramer acetate, natalizumab, fingolimod and dimethyl fumarate. These drugs have different clinical and adverse effects. Therefore, it is critical to select the appropriate DMD, and switching from one DMD to another in clinical practice requires careful monitoring. The Japanese guidelines for multiple sclerosis and neuromyelitis optica were revised in 2017, and a supplement to the guidelines for dimethyl fumarate was published in 2018. Herein, we review the characteristics of the six DMD available in Japan, and discuss their use according to the Japanese guidelines.

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Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies

Cited by 248 publications

References 20 publications

AJM300, a novel oral antagonist of α4‐integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects

AJM300, a novel oral antagonist of α4‐integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Disease‐modifying drugs for multiple sclerosis in Japan: A focus on the 2017 Japanese guidelines and the 2018 supplement

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