Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial

Miller, David H.; Weber, Thomas K.; Grove, Richard; Wardell, C.; Horrigan, Joseph P.; Graff, Ole; Atkinson, Gillian; Dua, Pinky; Yousry, Tarek; MacManus, David; Montalbán, Xavier

doi:10.1016/s1474-4422(11)70299-x

Cited by 73 publications

(52 citation statements)

References 25 publications

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“…In contrast to natalizumab, firategrast is taken orally and is short-acting, providing differences in bioavailability and pharmacodynamics. Results from a randomized, double-blind, placebo-controlled, phase II study in 343 patients with RRMS showed that the highest dose of firategrast resulted in a significantly lower cumulative number of new gadolinium-enhancing lesions (49 %) [105]. However, experience from the phase II natalizumab trial reported a 92 % reduction [106], pointing towards a lower efficacy of firategrast than expected.…”

Section: Therapies Aiming At T-lymphocyte Migration [Anti-α4β Integrimentioning

confidence: 98%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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Section: Therapies Aiming At T-lymphocyte Migration [Anti-α4β Integrimentioning

confidence: 98%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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“…For this Phase II, industry-sponsored, multicenter trial, researchers randomized 343 RRMS patients to receive twice-daily placebo or firategrast at low dose (150 mg), middle dose (600 mg) or high dose (900 mg for women, 1200 mg for men) [164]. Active treatment lasted 24 weeks.…”

Section: Firategrastmentioning

confidence: 99%

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

D’Amico

Leone

Caserta

et al. 2015

Expert Review of Neurotherapeutics

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Multiple sclerosis (MS) is characterized by demyelination and axonal loss that results in progressive disability. Recent advances in understanding the immune pathogenesis of MS resulted in the introduction of numerous effective drugs with diverse mechanisms of actions, routes of administration and benefit-risk profiles. New oral drugs recently approved for MS treatment has led to significant achievements in MS management. The oral route of administration promotes patient satisfaction and increases therapeutic compliance; but their introduction has raised concerns regarding safety and tolerability; and a thorough analysis of the benefit/risk ratio is required. This article reviews the mechanisms of action, safety and efficacy of the licensed and experimental oral drugs in MS. Moreover, we put into perspective the disease, drug and patient-related factors that should be taken into account when considering the appropriate oral drug and treatment strategy to the appropriate patient, thus paving the road for personalized medicine in MS.

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“…A phase 2 proof-of-concept trial of firategrast an oral antiα4βintegrin agent in relapsing remitting MS was reported recently [54]. Three-dose arms of firategrast were compared with placebo.…”

Section: Future Prospectsmentioning

confidence: 99%

Natalizumab Therapy for Multiple Sclerosis

Chataway

Miller

2013

Neurotherapeutics

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The treatment of relapsing remitting multiple sclerosis has witnessed major progress since the first effective disease modifying treatment, ß-interferon, became available in 1993. One of the most remarkable new treatments has been natalizumab. This review describes the evolution of this humanized anti-α4ß1 monoclonal antibody, from preclinical experimental research through proof-of-concept (phase 1/2) and pivotal (phase 3) clinical trials to the now extensive experience of its use in clinical practice. The future potential and challenges of natalizumab and oral therapies with a similar mechanism of action are also discussed.

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Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial

Cited by 73 publications

References 25 publications

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal

Natalizumab Therapy for Multiple Sclerosis

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