COVID-19

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 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 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^1-3
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 three main categories: (1) mRNA based, (2) viral-vector vaccines, and (3) inactivated vaccines
There is currently no report on efficacy or safety of SARS-CoV-2 vaccines in immunocompromised persons or in patients receiving immunomodulatory drugs
As with inactivated vaccines, the use of viral-vector-, or mRNA based SARS-CoV-2 vaccines in patients receiving immunomodulant/immunosuppressant therapies such as siponimod may have a diminished immune response
- The use of non-live vaccines is not contraindicated^4,5
- The use of non-live vaccines are not prohibited in the EXPAND study and some participants received inactivated vaccines during the clinical trial⁶
Vaccination against SARS-Cov-2 should be considered on a case-by-case basis at the discretion of the physician and according to the guidelines in the local vaccine product prescribing information⁷
The physician should take into account the individual benefit-risk assessment of either interrupting siponimod or continuing siponimod⁸
- When stopping siponimod for vaccination, the possible return of disease activity should be considered
- Vaccinations may be less effective if administered during siponimod treatment. Discontinuation of siponimod for 1 week prior to planned vaccination until 4 weeks after vaccination did not compromise the efficacy of an influenza vaccination^4,6,9
For patients getting started on siponimod, it is recommended to initiate treatment at least 4 weeks following the second dose of SARS-CoV-2 vaccine^4,8,9

Based on the totally available data from the COVID-19 case reports in the postmarketing setting and comprehensive data analysis by MS Data Alliance GDSI¹⁰:

A final 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

Clinical trials

As of 27-December-2020, 9 patients reported COVID-19 infection in the ongoing clinical trials¹¹

Age mean (range): 46.7 years (26-60);
Female/male: 8/1
Of the 9 confirmed COVID-19, 7 are non-serious (Grade 1-2), 2 reported SAEs
7 of 9 patients recovered; siponimod was temporarily interrupted in 2 patients

Postmarketing

As of 27-December-2020, 45 patients reported COVID-19 infection during postmarketing exposure¹¹

Age mean (range): 54 years (31->70y);
Female/male: 25/14 (not reported in 6 cases)
Of the 45 confirmed COVID-19, 34 are non-serious; 11 are serious
- 3 fatal outcomes^*(COVID registry- 2 patients aged >50 and >70 years; no further details provided; third patient was 60 years old with morbid obesity, diabetes and hypertension)
- All remaining patients, where information was provided, recovered or were asymptomatic; siponimod is ongoing in 8 patients, discontinued in 7 patients, and was temporarily interrupted in 3 patients (information not provided in 2 patients)

*Based on SARS-CoV2 test positive, or noted to be diagnosed with COVID-19
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 Argus 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 siponimod is not readily available. Many of the cases contain very limited information and includes cases that are lost to follow up. 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

As of 27-December-2020, with a cumulative exposure of over 3000 patient-years, 54 confirmed cases of COVID-19 (45 post marketing and 9 clinical trials) have been reported in the Novartis Safety Database¹¹

COVID-19 infection confirmed cases¹¹

**Ascertained based on the most serious criteria; ^For two patients only patient age was available (>50 year and >70 years); third patient was 60 years old morbidly obese female with diabetes and hypertension; ^#One patient with fatal outcome was noted to be also hospitalized; ^§Four patients had contributory comorbidities; no information on medical history provided in the other 4 patients; ^¶Patient had mild symptoms and was not hospitalized; ^ǁImportant medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other serious outcomes; ^ɭReceived from non-HCP

COVID-19 severity and outcome¹¹

^ʄCOVID-19 severity was assessed based on both the FDA and WHO COVID-19 criteria; ^ǂInformation as per the last follow-up; ^ʆvent or ICU includes patients on monitored floor, CPAP
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 Argus 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 siponimod is not readily available. Many of the cases contain very limited information and includes cases that are lost to follow up. 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

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.¹² The current COVID-19 pandemic has raised concerns regarding the immune response to viral infections in MS patients treated with these therapies¹³
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.¹⁰The 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
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 symptoms¹⁴

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; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; vent, ventilation

References

1. World Health Organization. Coronavirus disease (COVID-19) outbreak. Accessed June 4, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
2. European Centre for Disease Prevention and Control. COVID-19. Accessed June 4, 2020. https://www.ecdc.europa.eu/en/novel-coronavirus-china
3. 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
4. Siponimod^® Prescribing Information. Accessed February 10, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf.
5. Ufer M, et al. Neurol Neuroimmunol Neuroinflamm. 2017;4(6):e398.
6. Novartis Data on File
7. Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the United States. Last updated February 10, 2021. Accessed February 10, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html
8. 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
9. Siponimod Summary of Product Characteristics. Accessed February 10, 2021. https://www.ema.europa.eu/en/documents/product-information/mayzent-epar-product-information_en.pdf
10. 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.
11. Data on File, cutoff date 27-Dec-2020, Novartis Pharma AG.
12. Oh J, et al. Curr Opin Neurol. 2018;31(6):752-759.
13. Rostami Mansoor S, Ghasemi-Kasman M. J Med Virol. 2020;12. doi: 10.1002/jmv.26593.
14. MS International Federation. COVID-19. Last updated on January 13, 2021. Accessed February 15, 2021. http://www.msif.org/wp-content/uploads/2021/01/Jan-2021-MSIF-Global-advice-on-COVID-19-for-people-with-MS-FINAL.pdf