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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

Clinical trials and Open-label extension

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

*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

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, 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