COVID-19backup | Siponimod Global Safety Site

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 September 25, 2021, with a exposure of over 9,000 patient-years, a total of 115 cases, either confirmed**(n=107) or suspected^ (n=8) COVID-19 were identified with siponimod treatment in the postmarketing setting.² There were 37 cases from ongoing clinical trials, with 35 confirmed** and two suspected^ cases as of May 28, 2021.³

Postmarketing experience

Clinical trials and Open-label extension

Of the 107 confirmed COVID-19 cases, 24 were serious cases

Age mean (range): 53 years (31-74; based on 83 cases where information was provided)
Female/male: 68/30 (9 not reported)
35 cases recovered/recovering, 4 patients’ condition was unchanged, 3 patients had fatal outcomes, and the outcome in 65 cases was not reported

Of the 35 confirmed COVID-19 cases, 7 were serious cases

Age mean (range): 48 years (24-59)
Female/male: 68/30 (9 not reported)
33 cases recovered/recovering, and the outcome of 2 was not reported

**reported to have a SARS-CoV-2–positive test result or if the patient was reported to have been diagnosed with COVID-19 in post marketing settings and positive laboratory confirmation through real-time polymerase chain reaction or serological test, as reported by treating physician in clinical trials
^without a positive test or a definitive diagnosis in postmarketing settings 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

^#Ascertained based on the most serious criteria
^§Age at time of event for postmarketing cases and age at study start for clinical trial cases
^¶Two CT patients and one PM patient with fatal outcome were also noted to be hospitalized
^ǁTwo patients from registry where only approximate age of the patient was provided (>50 years and >70 years); third patient was a 60-year-old morbidly obese female with diabetes and hypertension
^ɭThree cases with one or more COVID-19 risk factors; remaining cases did not provide any information regarding comorbidities
^ʄ Two cases received from non-HCPs
^ǂIncludes asymptomatic patients and patients reported to be doing well

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

Clinical response to COVID-19 vaccination

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 CTs, of the 208 patients who were vaccinated (includes 107 fully vaccinated patients), 2 patients had breakthrough COVID-19 infection^ʆ (i.e., > 2 weeks after 2^nd dose of vaccine, or > 2 weeks after one dose of a single dose regimen)

One patient was a 55-year-old female with EDSS-4.5 reported with moderate COVID-19 who recovered while therapy with siponimod was continued
The second patient was a 50-year- old obese female with debilitating MS (EDSS-7.5) who had a fatal outcome due to COVID-19 pneumonia

^ʆClinical trial case severity was based on the investigator-reported severity using the CTCAE (Common Terminology Criteria for Adverse Events) grades: 1 = mild; 2 = moderate; 3 = severe; 4 = life threatening; 5 = fatal. Note that CTCAE grades of 4 or 5 were categorized in the table as critical.

Note: No reliable information or estimates of number of siponimod 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 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%^7,8
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 symptoms⁹

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^10-12
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. A first interim analysis results were presented at ECTRIMS 2021. (AMA-VACC)¹³
The incidence of breakthrough infections in fully vaccinated plwMS varies from 0.04% to 1.1% with mild to moderate course in most cases,^14,15,16 The rate of breakthrough infections in fully vaccinated general population varies from 1/100 to 1/5,000¹⁷ with majority being mild or moderate and mortality ranging from 0.001% to 6.3%.^18,19,20
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^21,22
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 infections²³
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 label²⁴
- 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 countries⁸
An individual benefit-risk assessment should be made in relation to either interrupting siponimod or continuing siponimod treatment²⁰^,25
- 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
For patients getting started on siponimod, it is recommended to initiate treatment at least 4 weeks following the full course of SARS-CoV-2 vaccine^21,25,26
The use of live attenuated vaccines should be avoided for patients on siponimod and for 4 weeks after stopping treatment^21,25
A full course of vaccination with varicella vaccine is recommended for antibody-negative patients prior to commencing treatment with siponimod^21,25

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-September-2021, Novartis Pharma AG.
3. Data on File, cutoff date 28-May-2020, Novartis Pharma AG.
4. Oh J, et al. Curr Opin Neurol. 2018;31(6):752-759 doi: 10.1097/WCO.0000000000000622 https://journals.lww.com/co-neurology/Fulltext/2018/12000/Multiple_sclerosis__clinical_aspects.15.aspx
5. Rostami Mansoor S, et al. J Med Virol. 2020;12. doi: 10.1002/jmv.26593 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675642/
6. Reder A.T et al. CNS Drugs (2021) https://doi.org/10.1007/s40263-021-00804-1
7. Bsteh G et al. PLoS ONE 2021. https://doi.org/10.1371/journal.pone.0255316 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255316
8. Sormani MP et al. Annals of Clinical and Translational Neurology 2021.doi: 10.1002/acn3.51408
9. MS International Federation. COVID-19. Updated November 19, 2021. Accessed November 25, 2021. http://www.msif.org/wp-content/uploads/2021/06/June-2021-MSIF-Global-advice-on-COVID-19-for-people-with-MS-FINAL.pdf
10. World Health Organization. Coronavirus disease (COVID-19) outbreak. Accessed June 4, 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
11. European Centre for Disease Prevention and Control. COVID-19. Accessed June 4, 2020. https://www.ecdc.europa.eu/en/novel-coronavirus-china
12. 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
13. Ziemssen T, et al. Poster presented at ECTRIMS 2021; P810
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. SARS-CoV-2 Vaccine Breakthrough Surveillance and Case Information Resource (wa.gov). Accessed on 25 November 2021
19. Breakthrough cases: Tracking disease infection after vaccination | SCDHEC. Accessed 25 November 2021
20. Mark W. Tenforde et al. JAMA. 2021;326(20):2043-2054. doi:10.1001/jama.2021.19499
21. Siponimod Summary of Product Characteristics. Novartis Pharmaceuticals Corp; 2020. Accessed February 10, 2021. https://www.ema.europa.eu/en/documents/product-information/mayzent-epar-product-information_en.pdf
22. Ufer M, et al. Neurol Neuroimmunol Neuroinflamm. 2017;4(6):e398.
23. Novartis Data on File. EXPAND core CSR Novartis Pharmaceuticals Corp.
24. 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
25. Mayzent Prescribing information. Novartis Pharmaceuticals Corp; 2020.
26. 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