S1P receptor modulators in Multiple Sclerosis: Detecting a potential skin cancer safety signal

Stamatellos, Vasileios-Periklis; Rigas, Antigony; Stamoula, Еleni; Lallas, Aimilios; Papadopoulou, Athina; Papazisis, Georgios

doi:10.1016/j.msard.2022.103681

Cited by 13 publications

(9 citation statements)

References 38 publications

(45 reference statements)

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“… 28 – 30 A study of S1P modulators suggests there may be an association with an increase in risk of skin cancers, particularly basal cell carcinomas. 31 Similar to the general population, basal cell carcinomas were the most frequent cancer type reported in ozanimod clinical trials (IR 103.6/100,000 PY). The estimated incidence of basal cell carcinoma in the general population ranges from 25 to 321 per 100,000 PY in European and US populations.…”

Section: Discussionmentioning

confidence: 90%

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial

et al. 2022

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Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. Objective: To characterize long-term safety and efficacy of ozanimod. Methods: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. Results: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. Conclusions: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity.

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Section: Discussionmentioning

confidence: 90%

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial

et al. 2022

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“…48 While there are reported cases of melanoma, such as a Dutch series of five patients using fingolimod for over a year (12-32 months) without deep lymphopenia (lymphocytes >0.5 G/l), 58 data from the literature generally suggest a warning signal for skin cancers without an increased risk of melanoma in patients followed up for 4.5 years. 59 Data extracted from the FAERS database from 2004 to 2020 were reported to indicate a safety signal concerning skin cancer (adjusted OR = 4.54 (3.86-5.32)) 60 with fingolimod compared with other DMTs, and another retrospective study supported this finding. 41 In 2021, an analysis of the same registry did not find an increased risk of "all-cause" cancer in patients taking fingolimod compared with interferon beta-1a, which served as a reference (adjusted OR = 0.61 (0.53-0.70)).…”

Section: Additional Inquiries Related To Question 1: Does Ms Increase...mentioning

confidence: 88%

Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society

Collongues,

Durand-Dubief,

Lebrun-Frenay

et al. 2024

Mult Scler

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Background: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. Objective: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). Methods: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. Results: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. Conclusion: These recommendations propose a strategic approach to managing cancer risk in PwMS.

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“…The potential impact of the long-term use of S1PR modulators on the risk of cancer and on cancer prognostic appears to be low, but needs further clarification [ 91 ]. Available data, however, suggest an increased risk of skin cancer in S1PR modulators users, especially basal cell carcinoma, and possibly also melanoma [ 93 ]. Considering this, dermatologic evaluation is needed prior to treatment initiation and periodically thereafter [ 17 , 18 , 93 ].…”

Section: Considerations On Other Risks and Risk Mitigation Strategies...mentioning

confidence: 99%

“…Available data, however, suggest an increased risk of skin cancer in S1PR modulators users, especially basal cell carcinoma, and possibly also melanoma [ 93 ]. Considering this, dermatologic evaluation is needed prior to treatment initiation and periodically thereafter [ 17 , 18 , 93 ].…”

Section: Considerations On Other Risks and Risk Mitigation Strategies...mentioning

confidence: 99%

An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis

Dumitrescu

Παπαθανασίου

Coclitu

et al. 2023

Expert Opinion on Pharmacotherapy

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Introduction Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. Areas covered Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. Expert opinion S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

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S1P receptor modulators in Multiple Sclerosis: Detecting a potential skin cancer safety signal

Cited by 13 publications

References 38 publications

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial

Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society

An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis

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