Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial

Cohen, Jeffrey A.; Arnold, Douglas L.; Comı, Gıancarlo; Bar‐Or, Amit; Gujrathi, Sheila; Hartung, Jeffrey; Cravets, Matt; Olson, Allan; Frohna, Paul; Selmaj, Krzysztof

doi:10.1016/s1474-4422(16)00018-1

Cited by 166 publications

(140 citation statements)

References 25 publications

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“…Last but not the least, the activation of S1PR3 by fingolimod was at least partially responsible for its side effects on the cardiovascular system and organ fibrosis, which may cause prominent safety issues. [19][20][21][22] RP101075 is S1PR1 selective and has extremely low affinity to other subtypes of S1PRs such as S1PR3. 27 The clinical pharmacokinetic properties of RP101075 are characterized by a Tmax of ≈7 hours and a half-life of 19 hours.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, many adverse events, including hypertension, macular edema, pulmonary toxicity, and hepatotoxicity, have been associated with fingolimod, because of its off-target interactions with other S1PR subtypes, particularly with S1PR3. [19][20][21][22] Considering that disorders such as coronary artery disease are relatively common among ICH patients, 23 the clinical application of fingolimod in these patients is limited.…”

Section: Strokementioning

confidence: 99%

“…25 Of interest, distinguished from fingolimod, RPC1063 has a reduced first-dose effect on heart rate with a dose-titration regimen and does not cause QTc prolongation, as demonstrated in a thorough clinical QT study. 20,[24][25][26] The profibrotic activity observed in heart and lung in patients treated with fingolimod was also not observed after RPC1063 treatment, suggesting its superior safety features versus fingolimod. 24 RP101075 is an active metabolite of RPC1063 with high potency and S1PR1 selectivity (>100-fold over S1PR5 and >10 000-fold over S1PR 2, 3, and 4).…”

Section: Strokementioning

confidence: 99%

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Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Sun

Shen

Han

et al. 2016

Stroke

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Intracerebral hemorrhage (ICH) is a devastating disease, which accounts for ≈10% to 15% of strokes with high mortality and morbidity.1,2 Effective treatments for ICH remain sparse.1 Accumulating evidence has demonstrated that brain inflammation provoked by microglia and infiltrating lymphocytes exacerbates ICH-induced brain injury.3 After ICH, brain-intrinsic microglia are the first immune responder and followed by inflammatory infiltrates such as neutrophils, monocytes, macrophages, and subsets of lymphocytes. 4,5 Activation of these cellular components together with factors they produce and cell death products, further contribute to brain inflammation, which results in the development of perihematomal edema.3-7 Perihematomal edema can aggravate the mass effect and secondary brain injury through subsequent oligemia and inflammatory insults.1,8 Edema, as a surrogate marker for inflammation in ICH, 1,9,10 and the persistence of perihematomal edema after ictus makes it amenable for intervention.1 Thus, targeting inflammation could be a viable approach for treating ICH.Sphingosine-1-phosphate (S1P) is a ligand for 5 G-proteincoupled receptors: S1P receptors 1 to 5 (S1PR1-5) are responsible for numerous cell-intrinsic and extrinsic activities. 11,12 Fingolimod (FTY720, Glenya), an oral therapy for multiple sclerosis (MS), is a S1PR modulator that binds to S1PR1, 3, 4, and 5. The beneficial effects of fingolimod in MS may be mediated by S1PR1 expressed on lymphocytes, vascular endothelia, neurons, and glia.11 Recent preclinical and clinical studies have demonstrated that fingolimod can attenuate neurodeficits and brain edema in ICH. [13][14][15][16][17][18] However, it remains unclear whether immune modulations via S1PR1 are sufficient for fingolimod to provide Background and Purpose-Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH. Methods-ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2 −/− mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH. Results-RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced th...

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Section: Discussionmentioning

confidence: 99%

Section: Strokementioning

confidence: 99%

Section: Strokementioning

confidence: 99%

See 1 more Smart Citation

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Sun

Shen

Han

et al. 2016

Stroke

View full text Add to dashboard Cite

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“…Alemtuzumab produces rapid and profound lymphopenia lasting for years via antibody-dependent cellular cytotoxicity [13]. Alemtuzumab was compared to IFNβ-1a administered subcutaneously three times a week in two phase III trials of RRMS [24,25]. Alemtuzumab reduced the annualised relapse rate (ARR) by 49%-55%, MRI gadolinium enhancing lesions by 61%-63% and the rate of disability progression by 30%-42% [25,26].…”

Section: Approved Treatments In Ms Injectable Drugsmentioning

confidence: 99%

“…In a phase II trial in RRMS, siponimod was shown to reduce brain MRI lesions and relapses by up to 80 % compared to placebo [104]. Another oral selective S1P receptor modulator, ozanimod, was recently successfully tested in a phase 2 trial with positive MRI outcomes [24].…”

Section: Siponimod and Ozanimodmentioning

confidence: 99%

The future of multiple sclerosis treatments

Coclitu

Constantinescu

Tanasescu

2016

Expert Review of Neurotherapeutics

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Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis

Gonzalez-Lorenzo,

Ridley,

Minozzi

et al. 2024

Cochrane Database of Systematic Reviews

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Background Different therapeutic strategies are available for the treatment of people with relapsing‐remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015. Objectives To compare the efficacy and safety, through network meta‐analysis, of interferon beta‐1b, interferon beta‐1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta‐1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1‐a and beta 1‐b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS. Search methods CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top‐up search was conducted on 8 August 2022. Selection criteria Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS. Data collection and analysis Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta‐analysis. Certainty of the evidence was assessed by the GRADE approach. Main results We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo‐controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high‐certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate‐certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate‐certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate‐certainty...

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Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial

Cited by 166 publications

References 25 publications

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

The future of multiple sclerosis treatments

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis

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