COVID-19

Novartis routinely monitors cases of COVID-19 in patients on therapy with siponimod. Based on the totality of data available from the COVID-19 case reports in the clinical trials and postmarketing setting as well as comprehensive data analysis by MS Data Alliance GDSI¹

A conclusion cannot be drawn on the risk of COVID-19 in patients treated with siponimod compared to the general population
Available data indicates similar COVID-19 disease course in MS patients treated with siponimod compared to the general population

As of March 25, 2023, with an exposure of over >31,187 patient-years, a total of 579 cases, either confirmed**(n=571) or suspected^ (n=8) COVID-19 were identified in patients receiving siponimod treatment in the postmarketing setting.² There were 175 cases from ongoing clinical trials, with 173 confirmed** and two suspected^ cases as of March 25, 2023.³

Postmarketing experience

Clinical trials and Open-label extension

**based on reported preferred terms from the MedDRA narrow SMQ for COVID-19 in the post marketing setting and positive laboratory confirmation through real-time polymerase chain reaction or serological test, as reported by treating physician in clinical trials
^ based on reported preferred terms from the MedDRA narrow SMQ for COVID-19 in the postmarketing setting and absence of a positive SARS-CoV-2 test or definitive diagnosis but with signs and symptoms consistent with COVID-19 and SARS-CoV-2 infection in clinical trials

COVID-19: Confirmed cases^2,3

^#A case may have more than one seriousness criteria

This section provides a summary of cases of siponimod-treated patients either suspected as having or reported to have COVID-19 as reported in the Novartis safety database, including spontaneous reports submitted voluntarily, cases identified in the scientific literature, and cases from ongoing clinical trials. There is typically underreporting in this setting; therefore, the true numerator is unknown. The denominator is also unknown as the actual number of patients on therapy with siponimod is not readily available. Many of the cases contain very limited information, and cases lost to follow up are included. Therefore, due to these limitations, it is not possible to draw any meaningful conclusions concerning the incidence of COVID-19 or course of illness in patients receiving siponimod.

Vaccine response to COVID-19

Novartis routinely monitors COVID-19 vaccine clinical response in patients on therapy with siponimod received from clinical trials or from the post marketing setting.

In clinical trials, of the 357 fully vaccinated patients (an additional 50 patients received partial dose), 88 patients had breakthrough COVID-19 infectionʆ (i.e., ≥2 weeks after 2nd dose of vaccine, or ≥ 2 weeks after one dose of a single dose regimen). This includes one patient who had a fatal outcome, two cases reported outcome as not recovered and 85 patients outcome is reported as recovered.

Note: No reliable information or estimates of number of siponimod patients receiving COVID-19 vaccination in post-marketing setting is available.

Additional information

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Impact of COVID-19 in MS in a real-world setting

MS is an autoimmune, chronic inflammatory, neurodegenerative disorder of the CNS in which patients are generally treated with immunosuppressants or immunomodulators.⁴ The current COVID-19 pandemic has raised concerns regarding the immune response to viral infections and post-vaccination in patients with MS treated with these therapies⁵
Comprehensive data sharing and analyses regarding the effect of COVID-19 in people with MS has been conducted by the COVID-19 in MS – GDSI.¹ The GDSI is a joint initiative of the MS International Federation and the MS Data Alliance, acting under the umbrella of the European Charcot Foundation and in collaboration with many (data) partners across the globe
In people with MS, the incidence of COVID-19 varies from 0.5% to 1.13%.⁶ The mortality due to COVID-19 has been reported from 1.6% to 4.2%^6-9
- Prosperini L, et al. reported crude death rate of 1.97% and estimated indirectly-adjusted age-standardized lethality ratio to be 1.24 suggesting 24% increased risk of death from COVID-19 in patients with MS¹⁰. That excess of risk of mortality due to COVID-19 was confirmed by the Italian MusC-19 Study Group only for those patients who belonged to the ‘higher-risk- group' (EDSS > 3.0 or at least 1 comorbidity).⁶
According to the MS International Federation, the evidence available suggests that people with MS taking siponimod do not have an increased risk of more severe COVID-19 symptoms¹¹

Siponimod and COVID-19 – Guidance to HCPs

Novartis is committed to patients’ health and safety. In these unprecedented times, we are striving to keep patients, care partners, and health care providers up to date and provide the latest information to help inform decisions related to the use of our products. Novartis continues to collect data to address concerns related to the impact of COVID-19 on patients treated with siponimod
In general, patients and prescribers should act in accordance with local government and health authority guidance concerning the COVID-19 pandemic (including guidance on social distancing and self-isolation, as applicable). HCPs may also consult advice specific to patients with MS provided by international or local HCPs and patient organizations^12-14
HCPs should be aware that the immune system effects of siponimod, integral to the mechanism of action in MS, may increase the risk of infections (including viral infections), as disclosed in the product label
Novartis believes that treatment decisions should be made between a patient and their treating HCP based on a benefit-risk assessment specific to the individual patient

SARS-CoV-2 vaccination considerations

To date all of the SARS-CoV-2 vaccines currently approved and available or in development belong to several categories/platforms, namely (1) mRNA-based vaccines, (2) nonreplicating viral-vector vaccines, (3) inactivated vaccines and (4) protein vaccines, and (5) live attenuated vaccines
As with inactivated vaccines, the use of nonreplicating viral-vector vaccines or mRNA based SARS-CoV-2 vaccines in patients receiving immunomodulant/immunosuppressant therapies such as siponimod may have a diminished immune response
Novartis is conducting in Germany an open label, multicenter, clinical trial, to evaluate the humoral and cellular immune response post-vaccination (mRNA based vaccines) in people living with SPMS (active) receiving treatment with siponimod according to the regular clinical practice. New results of AMA-VACC study have been presented at different congresses during 2022. ¹⁵
- New information: AMA-VACC manuscript already available
To date the available data of the occurrence and severity of breakthrough infections after a full course of vaccination in people living with MS (plwMS) is very scarce. Its frequency varies from 2% for Delta variant to 6% for Omicron variant (Italian and Danish studies)^16,17
There is presently no contraindication for the use of inactivated, nonreplicating viral-vector, or mRNA-based SARS-CoV-2 vaccines while on treatment with siponimod, even if vaccinations may be less effective^18,19
There were patients who received non-live vaccines including SARS-CoV-2 concomitantly with the study drug during the EXPAND study (core and extension phases). Although vaccine immune response in those patients was not measured during the clinical study and is not available, Novartis is trying to gather all the relevant information concerning clinical outcomes in participants who received any of the available SARS-CoV-2 vaccines, with special attention to the occurrence and severity of the breakthrough infections²⁰
Vaccination against SARS-CoV-2 should be considered on a case-by-case basis at the discretion of the treating physician and should be in adherence to immunization guidelines in the local vaccine label²¹
- Please review local prescribing information for any specific SARS-CoV-2 vaccine and comply with local prescribing information requirements for specific contraindications and special warnings and precautions for use
- People with MS who are considered to be immunocompromised could be advised to receive an additional dose of COVID-19 vaccine depending on local recommendations of their countries⁷. In some countries other prophylaxis treatment could also be available as add-on strategy to minimize the risk of getting infected by SARS-CoV-2.
All immunizations should be administered according to local immunization guidelines and siponimod product information^18,22
The use of live attenuated vaccines should be avoided for patients on siponimod and for 4 weeks after stopping treatment^18,22
A full course of vaccination with varicella vaccine is recommended for antibody-negative patients prior to commencing treatment with siponimod^18,22
An individual benefit-risk assessment should be made in relation to either interrupting siponimod or continuing siponimod treatment²²^,23
- Stopping Treatment: Discontinuation of siponimod for 1 week prior to planned vaccination and until 4 weeks after is recommended. Patients should be observed for relevant signs of possible severe exacerbation or return of high disease activity upon siponimod discontinuation, and appropriate treatment should be instituted as required
- Reintroducing treatment: The duration of treatment interruption should be determined based on clinical judgment and evaluation of the risk-benefit of extending interruption vs reintroducing siponimod. The efficacy of the vaccine is not considered to be compromised if siponimod treatment is paused 1 week prior to vaccination until 4 weeks after. When reintroducing siponimod, local label and guidance should be referred for re-titration, which is required if the drug is interrupted for 4 or more consecutive days
The guidance provided by National Multiple Sclerosis Society (NMSS) suggests that people with MS who are fully vaccinated with a mRNA vaccine and using S1PR modulators, alemtuzumab, and anti-CD20 therapies may benefit from an additional dose of mRNA vaccine and from the use of Evusheld^ɭ (tixagevimab co-packaged with cilgavimab)
Regarding the use of REGEN-COV^ɭ (casirivimab and imdevimab, administered together) as post-exposure prophylaxis (preventative) for COVID-19, the NMSS suggests that it is safe to use with MS disease modifying therapies (DMTs), but the timing needs to be coordinated²³
In some countries, an additional dose of vaccine after being fully vaccinated in people with immunosuppressive conditions (due to their disease or their treatment)^24,25,26 and they are also considered some pre- and post-exposure prophylaxis^ɭ agents to be used in some people on higher risk of more severe course of COVID-19 (plwMS could be included in)²³

^ɭAll pre and post-exposure prophylaxis should be administered according to local guidelines and the corresponding product information.

Abbreviations

CNS, central nervous system; COVID-19, corona virus disease-19; CPAP, continuous positive airway pressure; GDSI, Global Data Sharing Initiative; HCP, health care professional; ICU, intensive care unit; mRNA, messenger ribonucleic acid; MS, multiple sclerosis; N, number; NA, not applicable; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

References

1. Simpson-Yap S, et al. First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes. Abstract submitted at: MSVIRTUAL 2020. available at https://cslide.ctimeetingtech.com/msdc2020/attendee/confcal/session/calendar/2020-09-26?q=COVID
2. Data on File, cutoff date 25-March-2023, Novartis Pharma AG.
3. Data on File, cutoff date 31-October-2022, Novartis Pharma AG.
4. Oh J, et al. Curr Opin Neurol. 2018;31(6):752-759 doi: 10.1097/WCO.0000000000000622
5. Rostami Mansoor S, et al. J Med Virol. 2020;12. doi: 10.1002/jmv.26593
6. Reder A.T et al. CNS Drugs (2021) https://doi.org/10.1007/s40263-021-00804-1
7. Sormani MP et al. Ann Neurol 2021. DOI: 10.1002/ana.26028
8. Bsteh G et al. PLoS ONE 2021. https://doi.org/10.1371/journal.pone.0255316
9. Simpson-Yap S, et al. Neurology 2021. 10.1212/WNL.0000000000012753.
10. Prosperini L et al. J Neurol. 2022. doi: 10.1007/s00415-021-10803-3
11. MS International Federation. COVID-19. Updated May 24, 2022. Accessed June 15, 2022. The coronavirus and MS - updated global advice (msif.org)
12. World Health Organization. Coronavirus disease (COVID-19) outbreak. Accessed June 4, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
13. European Centre for Disease Prevention and Control. COVID-19. Accessed June 4, 2020. https://www.ecdc.europa.eu/en/novel-coronavirus-china
14. US Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19). Accessed June 4, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html#clinical-management-treatment%3C
15. Ziemssen T, et al. Poster presented at AAN 2022
16. Sormani MP et al. eBiomedicine 2022, doi:10.1016/j.ebiom.2022.104042
17. Nina Breinholt Stærke 2022, Pre-print with THE LANCET, https://ssrn.com/abstract=4066425
18. Siponimod Summary of Product Characteristics. Accessed February 10, 2021.
https://www.ema.europa.eu/en/documents/product-information/mayzent-epar-product-information_en.pdf
19. Ufer M, et al. Neurol Neuroimmunol Neuroinflamm. 2017;4(6):e398. https://doi.org/10.1212/NXI.0000000000000398
20. Novartis Data on File. EXPAND core CSR Novartis Pharmaceuticals Corp.
21. Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the United States. Updated February 10, 2021. Accessed February 10, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html
22. Mayzent Prescribing information. Novartis Pharmaceuticals Corp; 2020.
23. National Multiple Sclerosis Society.MS, the coronavirus and vaccines – updated global advice. Accessed May 20, 2022. The coronavirus and MS – updated global advice (msif.org)
24. US Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. Accessed November 20, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised
25.United Nations. WHO advisory group recommends extra COVID-19 vaccine dose for immunocompromised. Accessed November 20, 2021. https://news.un.org/en/story/2021/10/1102732
26. Reuters. Factbox - Countries weigh need for booster COVID-19 shots. Accessed October 27, 2021. https://www.reuters.com/article/us-health-coronavirus-booster-idUKKBN2GA190