COVID-19 cases

Ocrelizumab and COVID-19 data

  • While it may still be too early to draw definitive conclusions, data we have reviewed from both internal and external sources (e.g. safety databases, RWD) suggest that COVID-19 follows a similar course in pwMS who are treated with ocrelizumab, with risk factors for severe COVID-19 similar to those observed in the general population1–11
    • These risk factors for severe COVID-19 include age >50 years and presence of select comorbidities, such as hypertension, chronic pulmonary disease, chronic kidney disease, diabetes, coronary heart disease, obesity and cancer 1–3,10
  • Patients receiving ocrelizumab who are either exposed to SARS-CoV-2 or confirmed to have COVID-19 should contact their neurologist or other medical professional right away. Patients should consult their neurologist or other medical professional before discontinuing their medication
  •  Ocrelizumab administration must be delayed in patients with an active infection until the infection is resolved12

Data collection

  • A combination of clinical trial, post-marketing and other external RWD provides the most comprehensive understanding of COVID-19 in patients receiving ocrelizumab 
    • Data from clinical trials are collected in a systematic fashion and are likely to be more comprehensive compared to spontaneous reports. In addition, the total population for which rates are calculated (i.e. the denominator) of the trial population is known and the patients are generally well-characterised
    • Post-marketing data are important because they allow for safety data collection in a real-world setting (in a more diverse population). The exact denominator is not known, and the data are dependent on voluntary reporting and spontaneous reports, which are often more biased towards serious cases
    • Real-world data have the potential to inform COVID-19 research and address particularly important questions for the medical and patient communities. This includes the clinical course and outcomes of patients with MS and COVID-19, and risk factors (clinical or treatment-related) potentially leading to a higher risk of severe COVID-19
  • We are continuously assessing data from our own pharmacovigilance database consisting of both clinical trial and post-marketing data (spontaneous reports and reports from non-interventional studies), as well as emerging data from external RWD studies
  • There is no evidence that ocrelizumab increases the risk of fatal COVID-19 outcomes3,6–9,13–15

Clinical trials

  • Clinical trials provide information based on select populations managed in closely controlled settings, and are intended to inform clinical practice in wider groups of patients with MS
  • A delay may exist with the standard reporting of AEs compared with SAEs. The majority of non-serious COVID-19 cases were received in October and November 2020, coinciding with the time that the data-cut was prepared from the pooled clinical trial data. Therefore, the SAE reporting dynamic reflects the global waves of the COVID-19 pandemic
  • As there is no implementation of mass testing in clinical trials, and no guidance to systematically report asymptomatic positive polymerase chain reaction tests as adverse events, the clinical trial data is not comparable with MS registries

Rates of COVID-19 in ocrelizumab-treated patients1,2

  • As of 27 November, 2020, 193 suspected or confirmed cases of COVID-19 were identified in 3,974 patients in 10 ongoing ocrelizumab clinical trials (5% of the trial population). Overall, 81.3% (157/193 cases) were subsequently classified as confirmed COVID-19 infections. The median (range) time since the first ocrelizumab dose was 3.6 years (0.5–11.6) in ocrelizumab-treated patients with COVID-19 infection compared to 3.0 years (0–12.4) in the overall population
    • No association between symptomatic COVID-19 infection and time since first ocrelizumab dose was observed (OR=1.03, 95% CI: 0.88–1.22, p=0.68)
  • There is an association between increasing number of comorbidities and greater risk of developing symptomatic COVID: one comorbidity (OR=1.68, 95% CI: 1.15–2.47, p<0.01) or ≥2 comorbidities (OR: 2.25, 95% CI:1.09–4.66, p=0.03)

Seriousness, severity and outcomes of ocrelizumab-treated patients with COVID-19 infection1

  • In the pool of ocrelizumab clinical trials, there were 193/3,974 cases of suspected or confirmed COVID-19, of which there were 57 (29.5%) cases of serious† COVID-19
    • The majority of cases (168/193, 87.0%) had recovered or were recovering at the time of the report
    • Overall, 40/57 (70.2%) of the serious cases had recovered or were recovering at the time of the report
  • Of the symptomatic COVID-19 cases, 127 (65.8%) were mild or moderate, 39 (20.2%) were severe, 7 (3.6%) were life-threatening, and 13 (6.7%) were fatal. Information on severity was unknown in seven (3.6%) cases
    • Of the serious cases of COVID-19, 4 (7.0%) were mild or moderate in severity, 33 (57.9%) were severe, 7 (12.3%) were life-threatening, and 13 (22.8%) were fatal

Post-marketing reports1

  • Post-marketing pharmacovigilance data are important because they allow for safety data collection in a real-world setting
  • Strengths in this data collection method include a broad pool of reporters, global coverage, standardised AE reporting form, including standardised assessment of seriousness and severity, as well as follow-up of cases with missing information
  • However, AE reporting is voluntary and post-marketing pharmacovigilance reports often provide incomplete information
    • The exact denominator is not known, and the data are dependent on voluntary reporting and spontaneous reports which are often biased towards more severe cases
    • Despite enhanced follow-up, missing information remains an issue

COVID-19 cases in ocrelizumab-treated patients1,2

  • As of 30 November, 2020, 613 cases of COVID-19 in ocrelizumab-treated patients were identified in the post-marketing setting
  • Overall, 568 cases were classified as confirmed COVID-19 cases, and 45 as suspected COVID-19 cases
  • More than 200,000 pwMS have been treated with ocrelizumab globally, in clinical trial and real-world, post-marketing settings1

Severity and outcomes of COVID-19 in ocrelizumab-treated patients1,2

  • Of 613 reported cases, a total of 202 (33.0%) required hospitalisation (Table 1), 11.4% of these hospitalised cases were asymptomatic, mild or moderate in severity
  • Outcomes were known in 74.4% (456/613) of the cases
  • The majority of these patients (383/613; 62.5%) had recovered, or were recovering, at data
    cut-off (Table 1)

                Table 1: Severity and outcomes of COVID-19 in ocrelizumab-treated patients1,2

Table 1: Severity and outcomes of COVID-19 in ocrelizumab-treated patients1,2

*Severity categories were assigned as follows: asymptomatic, if it was explicitly stated that no symptoms were present; mild, if
non-hospitalised symptom such as low-grade fever or cough were described; moderate, if shortness of breath was reported; severe, if pneumonia was present; critical, if requiring intensive care and/or mechanical ventilation. In patients hospitalised due to COVID-19 in the general population, published mortality rates range from 9.7% to 27.0%4,10,16–18.
Data presented as of 30 November, 2020.
 

  • As observed in the general population, in patients treated with ocrelizumab increased disease severity was associated with a stepwise increase in median age
    • Median age was 41.0, 46.0, 52.0 and 57.5 in patients with asymptomatic/mild/moderate disease, severe disease, critical disease, and fatal disease, respectively

Figure 1: Severity of COVID-19 according to age in ocrelizumab-treated patients1

Figure 1: Severity of COVID-19 according to age in ocrelizumab-treated patients1

Details of the 13 cases with a fatal outcome in clinical trials1

  • The majority of the cases with fatal outcomes (76.9%; 10/13) occurred in patients >50 years of age or with one or more risk factors associated with severe
    COVID-19 outcomes in the general population (e.g. age >50 years, hypertension, chronic pulmonary disease, chronic kidney disease, diabetes, coronary heart disease, obesity and cancer)
  • Characteristics of patients with severe COVID-19 in the general population are broadly reflected among the ocrelizumab clinical trial participants with serious or fatal COVID-191–4,11,16

Details of the 32 cases with a fatal outcome in post-marketing setting1

Of the cases with a fatal outcome in the post-marketing setting, 78.1% (25/32) occurred in patients over 50 years of age or with one or more risk factors associated with severe COVID-19 outcomes in the general population (e.g. age >50 years, hypertension, chronic pulmonary disease, chronic kidney disease, diabetes, coronary heart disease, obesity and cancer)

  • As in the general population, fatal outcomes were more likely in male patients >50 years of age or those with other underlying risk factors1–4,11,16

COVID-19 cases in the general population and from MS registries

  • From the real-world evidence available globally (Table 2), the MS population in general does not seem to be at higher risk from a fatal COVID-19 disease course (Table 3)
  • The fatality rates of pwMS treated with ocrelizumab are within the expected ranges for the MS populations

Table 2: Number of cases and deaths in the general population19

Table 2: Number of cases and deaths in the general population19
 Table 3: Number of cases and deaths in MS data sets, including reported ocrelizumab cases
Table 3: Number of cases and deaths in MS data sets, including reported ocrelizumab cases

*Louapre C, et al. JAMA Neurol 2020;77:1079–88; Sormani MP, et al. Ann Neurol 2021;89:780–9;
Hughes R, et al. Mult Scler Relat Disord 2021;49:102725; §Salter A, et al. JAMA Neurol 2021;78:699–708;
Simpson-Yap, et al. medRxiv 2021;doi:10.1101/2021.02.08.21251316v1;The US CoViMS registry data were included in the Data Sharing Initiative study contributing up to 50% of all cases and fatalities included in the analyses.


Limitations of COVID-19 real-world data: general population and MS datasets

  • Although real-world data emerging on COVID-19 in pwMS can provide valuable information, there are some inherent limitations (and biases) that are important to recognise when assessing the data.20,21 The differences in these findings are to be expected due to the challenges of collecting, analysing and interpreting
    real-world data
    • Real-world evidence can be challenging to interpret due to the potential for limitations in the datasets, including significant unknown and/or unreported data, differences in data collection and reporting (patient reported vs healthcare professional reported), suspected vs confirmed COVID-19 cases, identification of other comorbidities, and generally a reporting bias toward more severe cases
    • Due to countries and certain regions being affected differently by the pandemic, there may be differences in emerging data and interpretations
  • Publication of the real-world evidence in peer-reviewed journals will provide a robust assessment of the data quality and analytical methods, especially accounting for potential confounders and biases, which is essential to understand the impact of COVID-19 in pwMS

Prescribing Information

Indications vary in different countries. The local prescribing information from your country is the primary source of information on the known and potential risks associated with ocrelizumab.
M-XX-00005362 (Date of preparation: August 2021)

*Logistic regression adjusted for EDSS, sex, age, BMI, time since first ocrelizumab dose, subregion, number of comorbidities, study. Number of comorbidities: Comorbidities were selected from a COVID-19 specific list of adverse event terms within the SOCs ‘metabolism and nutrition disorders', ‘respiratory, thoracic and mediastinal disorders', ‘vascular disorders', 'cardiac disorders’, or ‘nervous system disorders’;
The validity and seriousness of cases were assessed according to the ICH guidelines.22

AE, adverse event; BMI, body mass index; CA, Canada; COVID-19, coronavirus disease 2019; EDSS, Expanded Disability Status Scale;
EHR, electronic health records; ICH, The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use;
Mex, Mexico; MSIF, MS International Federation; OR, odds ratio; pwMS, people with MS; RWD, real-world data; SAE, serious adverse event;
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOC, standard of care; USA, United States of America.
References
 
  1. Roche data on file;
  2. Hauser SL, et al. Presented at EAN 2021 (Presentation OPR-206);
  3. Hughes R, et al. Mult Scler Relat Disord 2021;49:102725;
  4. Richardson S, et al. JAMA 2020;323:2052–9;
  5. Sormani MP, et al. Lancet Neurol 2020;19:481–2;
  6. Montero-Escribano P, et al. Mult Scler Relat Disord 2020;42:102185;
  7. Safavi F, et al. Mult Scler Relat Disord 2020;43:10219;
  8. Barzegar M, et al. Mult Scler Relat Disord 2020;45:102276;
  9. Sormani MP, et al. Ann Neurol 2021;89:780–9;
  10. Louapre C, et al. JAMA Neurol 2020;77:1079–88;
  11. Dalla Costa G, et al. J Neurol Sci 2020;41:1647–50;
  12. OCREVUS® [SmPC]. https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf. Accessed 5 July, 2021;
  13. Sepulveda M, et al. Neurol Neuroimmunol Neuroinflamm 2020;8:e954;
  14. Hughes R, et al. Mult Scler Relat Disord 2020;42:102192;
  15. Chaudry F, et al. J Neurol Sci 2020;418:117147;
  16. Chawla D, et al. medRxiv 2020;doi:10.1101/2020.07.17.20156265;
  17. ISARIC Clinical Characterisation Group, et al. medRxiv 2020;doi:10.1101/2020.07.17.20155218;
  18. Salje H, et al. Science 2020;369;208–11;
  19. Johns Hopkins Coronavirus Resource Center. Mortality analyses. https://coronavirus.jhu.edu/data/mortality. Accessed 5 July, 2021;
  20. Cohen JA, et al. Mult Scler 2020;26:23–37;
  21. Evans K. Drugs Real World Outcomes 2019;6:43–5;
  22. European Medicines Agency. ICH Harmonised Tripartite Guideline E2A. https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-15.pdf. Accessed 23 July, 2021.