Clone of COVID-19_Nov11 | Fingolimod Global Safety Site

Fingolimod and COVID-19

Novartis routinely monitors cases of Covid-19 in patients on therapy with fingolimod. Based on the totality of the data available from the COVID-19 case reports in clinical trial and post-marketing setting as well as comprehensive data analysis by the MS Data Alliance Global Data sharing initiative¹

A conclusion cannot be drawn if a higher risk of COVID-19 exists in patients treated with fingolimod compared to the general population
Available data indicates a similar COVID-19 disease course in MS patients treated with fingolimod compared to the general population

Post-marketing setting^a

*Cumulative patient exposure through 28th February 2022; **Excludes a 10 week old neonate with paternal exposure to fingolimod during pregnancy developed COVID-19 concurrently with beta hemolytic streptococcus infection and deep vein thrombosis. The neonate was hospitalized, treated, recovered and was discharged. It was reported that neonates father was COVID-19 positive.

As of 28^th February 2022, Novartis has received 1,045 confirmed or suspected COVID-19 cases in fingolimod-treated patients in the post-marketing setting^2*:
- 1,000 confirmed cases (SARS-CoV-2 test positive, or noted to be diagnosed with COVID-19) and includes registry (MS Registries in European Union: France, Germany, Poland and Sweden) and published cases
  - 375 cases were reported as serious (13 patients had fatal outcome) and 625 cases as non-serious
    - Age range from 11 years to 82 years**; (mean age, 43 years; based on 712 cases where information was provided)
    - 711 female; 249 male; 40 not reported
    - At the time of most recent follow up :
      - 13 patients had a fatal outcome
      - 428 patients recovered/recovering
      - 66 patients had condition unchanged
      - 8 patients had condition deteriorated
      - 485 patients outcome was not reported

In addition, there were 9 cases from the ongoing Clinical Trial³

In the 9 clinical trial cases

Age mean (range): 17 years (14-20)
Female/male: 4/5
9 cases recovered/recovering

^aThis section provides a summary of cases of fingolimod-treated patients either suspected as having or reported to have COVID-19 as reported in the Novartis safety database, including spontaneous reports submitted voluntarily and cases identified in the scientific literature. 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 fingolimod 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 fingolimod.

COVID-19 infection confirmed cases^2,3

* A case may have more than one serious criteria ; **PARADIGMS study: Safety and efficacy of fingolimod in pediatric patients with multiple sclerosis, Cutoff date 04 Aug 2021; ^#Excludes a 10 week old neonate with paternal exposure to fingolimod during pregnancy developed COVID-19 concurrently with beta hemolytic streptococcus infection and deep vein thrombosis. The neonate was hospitalized, treated, recovered and was discharged. It was reported that neonates father was COVID-19 positive.

Clinical response to COVID-19 vaccination

Novartis routinely monitors COVID-19 vaccine clinical response in patients on therapy with fingolimod received from clinical trials or from the post marketing setting.
None of the fully vaccinated subjects exposed to fingolimod in CT had breakthrough COVID-19 infection.

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

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

MS is an autoimmune, chronic inflammatory, neurodegenerative disorder of CNS where 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 disease modifying therapies⁵
Comprehensive data sharing and analyses regarding the effect of COVID-19 in people with MS have been conducted by the COVID-19 in MS - GDSI.¹ The GDSI initiative 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%^6,7
According to the MS International Federation, the evidence available suggests that people with MS taking fingolimod do not have an increased risk of more severe COVID-19 symptoms⁸

Fingolimod 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 healthcare 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 fingolimod
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 multiple sclerosis provided by international or local healthcare professional and patient organizations^9-11
HCPs should be aware that the immune system effects of fingolimod, integral to the mechanism of action in multiple sclerosis, 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 health care professional based on a benefit-risk assessment specific to the individual patient

Fingolimod and SARS-CoV-2 vaccination consideration

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; (2) non-replicating viral-vector vaccines; (3) inactivated vaccines; (4) protein vaccines, and (5) live attenuated vaccines
As with inactivated vaccines, the use of non-replicating viral-vector or mRNA based SARS-CoV-2 vaccines in patients receiving immunomodulant/immunosuppressant therapies such as fingolimod 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. A first interim analysis results were presented at ECTRIMS 2021 ('AMA-VACC')¹². Results of a second interim analysis were presented during 2022. For more information, please go to 'AMA-VACC'¹³
A second study was conducted by Novartis in the US to evaluate the humoral immune response to mRNA COVID-19 vaccines in siponimod-treated patients with advancing forms of RMS in the context of the phase 3b EXCHANGE trial: COVID-19 vaccination substudy. A first interim analysis results were presented at the Annual ACTRIMS Forum 2022. For more information, please go to 'COVID-19 vaccine EXCHANGE sub study'
New Information: 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.^18,19
There is presently no contraindication for the use of inactivated, (non-replicating) viral-vector, or mRNA-based SARS-CoV-2 vaccines while on treatment with fingolimod, even if vaccinations may be less effective^20,21
There were patients who received non-live vaccines including SARS-CoV-2 concomitantly with the study drug during the PARADIGMS 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 infections²²
Vaccination against SARS-CoV-2 should be considered on a case-by-case basis at the discretion of the treating physician and adhere to immunization guidelines in the local vaccine label²³
- 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 immunocompromised should receive an additional dose of COVID-19 depending on local recommendations of their countries⁸
- 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* (tixagevimab co-packaged with cilgavimab)
- Regarding the use of REGEN-COV* (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 coordinated²⁴
- In some countries, an additional dose of vaccine is recommended in people with immunosuppressive conditions (due to their disease or their treatment)^25,26,27 and there are also considered some pre- and post-exposure prophylaxis* agents used in some people on higher risk of more severe course of COVID-19 (plwMS could be included in this category)²⁴
  
  * All pre and post-exposure prophylaxis should be administered according to local guidelines and the corresponding product information.
An individual benefit-risk assessment should be made in relation to either interrupting or continuing fingolimod treatment^20,28
- Stopping treatment: If a decision is made for stopping fingolimod for vaccination, a 6 week interval without therapy is needed, based on half-life, to clear fingolimod from the circulation. Caution is also indicated when stopping fingolimod therapy due to the risk of a return of disease activity. If discontinuation of fingolimod is deemed necessary, patients should be monitored during this time for relevant signs of a possible return of disease activity
- Reintroducing Treatment: The duration of treatment interruption will depend on clinical judgment and evaluation of the risk/benefit of extending interruption vs reintroducing fingolimod. Vaccinations may be less effective if administered during fingolimod treatment and for up to 2 months after treatment with fingolimod. When reintroducing fingolimod, refer to local guidance on initiation of treatment to evaluate the need for first-dose monitoring, and for other treatment initiation guidance
For patients getting started on fingolimod, it is recommended to initiate treatment at least 1 month following the second dose of SARS-CoV-2 vaccine^20,28,29
- The use of live attenuated vaccines should be avoided for patients on fingolimod and for 2 months after stopping treatment^20,28
- A full course of vaccination with varicella vaccine is recommended for antibody-negative patients prior to commencing treatment with fingolimod^20,28
- Vaccination against human papilloma virus should be considered prior to treatment initiation with fingolimod taking into account vaccination recommendations

Abbreviations

CNS, central nervous system; COVID-19, corona virus disease-19; CPAP, continuous positive airway pressure; GDSI, Global Data Sharing Initiative; HCP, healthcare professional; ICU, intensive care unit; mRNA, messenger ribonucleic acid; MS, multiple sclerosis; plwMS, people living with MS; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

References

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2. Data on File, Novartis safety database, cutoff date 28th February 2022. Novartis Pharma AG.
3. Data on File, Novartis safety database, cutoff date 04-August-2021. Novartis Pharma AG.
4. Oh J, et al. Curr Opin Neurol. 2018;31(6):752-759.
5. Rostami Mansoor S, et al. J Med Virol. 2021;93:1314-1319.
6. Reder A.T et al. CNS Drugs (2021) https://doi.org/10.1007/s40263-021-00804-1
7. Sormani MP, Salvetti M, Labauge P et al. DMTs and COVID-19 severity in MS: a pooled analysis from Italy and France. Annals of Clinical and Translational Neurology 2021.
doi:10.1002/acn3.51408
8. MS International Federation. Global COVID-19 advice for people with MS. Last updated on 4 June 2021. Accessed 19-Nov-2021.
http://www.msif.org/wp-content/uploads/2021/06/June-2021-MSIF_Global-advice-on-COVID-19-for-people-with-MS_FINAL.pdf
9. World Health Organization. Coronavirus disease (COVID-19) outbreak. Accessed 4-Dec-2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
10. European Centre for Disease Prevention and Control. COVID-19. Accessed 4-Dec-2020. https://www.ecdc.europa.eu/en/novel-coronavirus-china
11. US Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19). Accessed 4-Dec-2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinicalguidancemanagement-
patients.html#clinical-management-treatment%3C
12. Ziemssen T, et al. Poster presented at ECTRIMS 2021; P810
13. Rauser B et al. AAN 2022, April 24-26, 2022. https://index.mirasmart.com/aan2022/PDFfiles/AAN2022-001304.html
14. Sormani MP et al. Oral presentation at ECTRIMS 2021
15. Weinstock-Guttman B et al. Poster presented at ECTRIMS 2021; P630
16. Ahmad Z Mahadeen et al. Poster presented at ECTRIMS 2021; P978
17. Breakthrough Infections: Coronavirus After Vaccination | Johns Hopkins Medicine. Accessed 25 November 2021.
18. Stærke NSea. Levels of SARS-CoV-2 antibodies among fully-vaccinated individuals with delta or omicron variant breakthrough infections: a prospective cohort study. Accessed on 23rd May 2022. Lancet (preprint). 2022
19. Sormani MP, Schiavetti I, Inglese M, et al. Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy. EBioMedicine 2022. doi:10.1016/j.ebiom.2022.104042
20. Fingolimod (Gilenya®) EU Summary of Product Characteristics. Last updated 3-August-2021. Accessed on 6-December-
2021 https://www.ema.europa.eu/en/medicines/human/EPAR/gilenya
21. Ufer M, et al. Neurol Neuroimmunol Neuroinflamm. 2017;4(6):e398.
22. Novartis Data on File. EXPAND core CSR Novartis Pharmaceuticals Corp.
23. 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
24. 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)
25. 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
26.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
27. Reuters. Factbox - Countries weigh need for booster COVID-19 shots. Accessed October 27, 2021. https://www.reuters.com/article/us-health-coronavirus-booster-idUKKBN2GA190
28. Mayzent Prescribing information. Novartis Pharmaceuticals Corp; 2020
29. National Multiple Sclerosis Society. Timing MS medications with COVID-19 mRNA vaccines. Accessed February 18, 2021. https://www.nationalmssociety.org/coronavirus-covid-19-
information/multiple-sclerosis-and-coronavirus/covid-19-vaccine-guidance/Timing-MS_Medications-with-COVID-19-mRNA_Vaccines

COVID-19