Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial

Kappos, Ludwig; Arnold, Douglas L.; Bar‐Or, Amit; Camm, John; Derfuss, Tobias; Kieseier, Bernd C.; Sprenger, Till; Greenough, K.; Ni, Pingping; Harada, Tomohiko

doi:10.1016/s1474-4422(16)30192-2

Cited by 68 publications

(93 citation statements)

References 32 publications

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“…No AV block of clinical concern was detected in either amiselimod group but one subject in the fingolimod group was withdrawn owing to highly frequent 2:1 AV blocks. To date, there have been no clinically significant AV blocks reported in amiselimod phase I and II studies . All of these findings suggested that amiselimod up to 0.8 mg is unlikely to induce any significant dromotropic effect in humans, although this hypothesis needs to be further validated in large‐scale and longer‐term studies.…”

Section: Discussionmentioning

confidence: 96%

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

Harada¹,

Wilbraham²,

Borderie³

et al. 2017

Brit J Clinical Pharma

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AimAmiselimod (MT‐1303) is a selective sphingosine 1‐phosphate 1 (S1P1) receptor modulator which is currently being developed for the treatment of various autoimmune diseases. Unlike some other S1P receptor modulators, amiselimod seemed to show a favourable cardiac safety profile in preclinical, phase I and II studies. The aim of the current study was to characterize the cardiac effects of amiselimod by directly comparing it with fingolimod and placebo.MethodsA total of 81 healthy subjects aged 18–55 years were equally randomized to receive amiselimod 0.4 mg, amiselimod 0.8 mg, placebo or fingolimod 0.5 mg once daily for 28 days. The chronotropic/dromotropic and inotropic effects were evaluated using intensive Holter electrocardiogram and echocardiography.ResultsUnlike fingolimod, neither amiselimod dose exerted acute (1–6 h) negative chronotropic effects on Days 1 and 2. The lowest nadir mean hourly heart rate was observed on Day 14 in the amiselimod 0.4 mg group (least squares mean difference: −4.40 bpm, 95% confidence interval −7.15, −1.66) and Day 7 in the 0.8 mg group [−3.85 bpm (−6.58, −1.11)] compared with placebo, but these changes were smaller than those with fingolimod on Day 1 [−6.49 bpm (−8.95, −4.02)]. No clinically significant bradyarrhythmia or cardiac functional abnormalities were observed in either amiselimod group. Both amiselimod doses were well tolerated and no serious adverse events were reported. Fingolimod was also generally well tolerated, although one subject was withdrawn owing to highly frequent 2:1 atrioventricular blocks on Day 1.ConclusionThe study demonstrated a more favourable cardiac safety profile for amiselimod than fingolimod when administered over 28 days in healthy subjects.

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Section: Discussionmentioning

confidence: 96%

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

Harada¹,

Wilbraham²,

Borderie³

et al. 2017

Brit J Clinical Pharma

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“…[20,21] With few late-stage assets currently being investigated, the overall advanced clinical development is dominated by anti-IL-17 and IL-23 for biologics and a variety of modes of action tested for oral agents (most of them still in phase 2: PF06700841 as oral JAK1/ TYK2 inhibitor, [22,23] Amiselimod (MT-1303) as S1P1 receptor antagonist [24] and GSK-2982772 as RIPK1 inhibitor. The advantages of bispecific antibodies are that they may be more selective, they may be efficacious at lower dosages, they may hit two or more pathways simultaneously, thus preventing escape mechanisms, and with specific modulation of their three-dimensional structure, pharmacokinetic properties of those antibodies may be intentionally determined.…”

Section: The Need For Multicomponent Therapymentioning

confidence: 99%

“…[92][93][94][95][96] Recently, the central role of STAT3 for the pathogenesis of psoriasis was reviewed [97] which also underlines the molecular link for most of the currently developed treatment strategies for psoriasis [22][23][24][25] to the pathophysiological role of various cells in the skin for the development of such an autoimmune disease. [92][93][94][95][96] Recently, the central role of STAT3 for the pathogenesis of psoriasis was reviewed [97] which also underlines the molecular link for most of the currently developed treatment strategies for psoriasis [22][23][24][25] to the pathophysiological role of various cells in the skin for the development of such an autoimmune disease.…”

Section: Th17 T Cells Cd8 + T Cells and Ilcs Plasmacytoid And Myeloidmentioning

confidence: 99%

Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

Florian

Flechsenhar

Bartnik

et al. 2019

Experimental Dermatology

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Due to the clinical development of drugs such as secukinumab, ustekinumab and dupilumab, major changes have been achieved in the treatment of patients diagnosed with psoriasis and atopic dermatitis. In academia and the pharmaceutical industry, research is increasingly moving towards the development of bispecific antibodies and multi‐specific nanobodies, as there is a compelling need for new treatment modalities for patients suffering from autoimmune or malignant disease. The purpose of this review is to discuss aspects of translational drug development with a particular emphasis on indications such as psoriasis and atopic dermatitis. The identification of biomarkers, the assessment of target organ pharmacokinetic and pharmacodynamics interactions and a wide range of in vitro, ex vivo and in vivo models should contribute to an appropriate prediction of a biological effect in the clinical setting. As human biology may not be perfectly reflected by approaches such as skin equivalents or animal models, novel approaches such as the use of human skin and dermal microperfusion assays in healthy volunteers and patients appear both reasonable and mandatory. These models may indeed generate highly translationally relevant data that have the potential to reduce the failure rate of drugs currently undergoing clinical development.

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“…Amiselimod has also shown efficacy with a favorable safety profile for relapsing MS patients. This compound is an S1P 1 modulator with a half-life between 380 and 420 h. A Phase 2 trial with a primary endpoint of assessing the number of gadolinium enhanced T1-weighted lesions on monthly MRI revealed positive outcomes with significant improvement seen on imaging of those who received drug compared to placebo [27]. …”

Section: Sphingosine-1-phosphate (S1p) Receptor (S1pr) Modulators mentioning

confidence: 99%

The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases

Mao-Draayer

Sarazin

Fox

et al. 2017

Clinical Immunology

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Multiple sclerosis (MS) is a prototype autoimmune disease of the central nervous system (CNS). Currently, there is no drug that provides a cure for MS. To date, all immunotherapeutic drugs target relapsing remitting MS (RRMS); it remains a daunting medical challenge in MS to develop therapy for secondary progressive MS (SP-MS). Since the approval of the non-selective sphingosine-1-phosphate (S1P) receptor modulator FTY720 (fingolimod [Gilenya®]) for RR-MS in 2010, there have been many emerging studies with various selective S1P receptor modulators in other autoimmune conditions. In this article, we will review how S1P receptor may be a promising therapeutic target for SP-MS and other autoimmune diseases such as psoriasis, polymyositis and lupus.

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Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial

Cited by 68 publications

References 32 publications

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

Cardiac effects of amiselimod compared with fingolimod and placebo: results of a randomised, parallel‐group, phase I study in healthy subjects

Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases

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