Ocrelizumab and Fatalities

Summary of Fatalities1,2

  • In ocrelizumab clinical trials, and their open-label extensions, there was no increase in fatalities in ocrelizumab-treated patients compared with controls
  • From the post-marketing experience there was no pattern observed in the causes of fatalities as reported to the regulatory authorities. 

Background Rates in the MS Population3,4

  • Estimated mortality rates in the overall MS population between 1968 and 2010 ranged from 0.37 per 100 patient-years to 0.9 per 100 patient-years
  • These estimates were based on an observational study in France (27,603 MS patients) and a retrospective study in the US (30,402 MS patients from the OptumInsight Research database)

The incidence rates of fatalities are derived from varied sources, and intended to provide context. Confounding factors which may influence mortality have not been accounted for; therefore, no direct comparisons should be made. Such factors may include, but are not limited to, type of MS, age, gender, disease duration, geographical region, population size, drug exposure, comorbid conditions, treatment history, and duration of follow-up.

Clinical Trials (Controlled Treatment Period and Open-Label Extension)

Incidence rate of fatalities in phase 3 clinical trials (controlled treatment period only)2

  OPERA I / OPERA II (Pooled)
Incidence rate per 100 PY (95% CI)
ORATORIO
Incidence rate per 100 PY (95% CI)
IFN β-1a Ocrelizumab Placebo Ocrelizumab
Phase 3  Controlled Treatment Period 0.14 (0.02,0.52) 0.07 (0,0.38) 0.41 (0.08,1.20) 0.25 (0.07,0.64)

a Two identical phase 3, global, randomised, double-blind, double-dummy studies with a 96-week controlled period during which 1,656 patients with relapsing forms of MS received either intravenous ocrelizumab (600 mg) every 24 weeks or subcutaneous interferon beta-1a (44 μg) three times weekly.5

b A phase 3, global, randomised, double-blind study with a ≥120-week controlled period during which 732 patients with primary progressive MS received either intravenous ocrelizumab (600 mg) or placebo every 24 weeks.6

Incidence rate of fatalities by exposure in clinical trials (controlled treatment period and open-label extension)1a

  Data Cut-off Datea Patients on Ocrelizumab (n) PY Fatalities (n) Incidence Rate per 100 PY 95% CIs

Ocrelizumab All-Exposure
Populationb

JUL 2015 2147 4484.5 8 0.178 0.077, 0.352
JAN 2016 2279 5710.7 8 0.140 0.060, 0.276
SEP 2016 2300 6940.9 11 0.158 0.079, 0.284
FEB 2017 2301 7747.8 13 0.168 0.089, 0.287
SEP 2017 3778 9473.5 16 0.169 0.097, 0.274
FEB 2018 3811 10,918.5 17 0.156 0.091, 0.249
JUL 2018
4501
12,558.9
19 0.151
0.091, 0.236
JAN 2019 4611 14,328.5 23 0.161 0.102, 0.241
JAN 2020 5680 18,218.4 26 0.143 0.093, 0.209

a Data cuts are cumulative; each data cut includes the previous cut and fatalities are included from both the controlled treatment period and open-label extension.

b Includes all patients exposed to ocrelizumab in the global and US MS clinical trials; excludes patients in compassionate use programme.

The causes of the fatalities in the all-exposure population are as follows: Suicide (n=6), cardiac arrest (n=2), metastatic pancreatic cancer (n=2), pneumonia (n=1), acute coronary insufficiency (n=1), adenocarcinoma of oesophagus (n=1), probable seronegative autoimmune encephalitis (n=1), aspiration pneumonia (n=1), bladder cancer (n=1), epileptic seizure (n=1), bronchopneumonia (n=1), MS disease progression (n=1), pulmonary embolism (n=1), systemic inflammatory response syndrome of undetermined origin (n=1), unknown (n=1), urinary infection/urosepsis (n=1), injury (n=1), medically assisted suicide (n=1), and fall (n=1)

Post-marketing Experience as of 31 July 2020

Incidence rate of fatalities by exposure in the post-marketing setting1*

  Market Perioda Patients on Ocrelizumab (n)b PY Fatalities (n)c Incidence Rate per 100 PY
Ocrelizumab Post-Marketing APR 2017–DEC 2017
~27,678
~8,899
24 0.27
APR 2017–MAR 2018
~37,171
~15,682
45 0.29
APR 2017–MAY 2018
~48,780
~23,776
64 0.27
APR 2017–JULY 2018
~58,667
~33,526
87 0.26
APR 2017–SEP 2018
~66,662
~43,560
114 0.26
APR 2017–DEC 2018
~78,544
~60,710
149 0.25
APR 2017–MAY 2019
~103,290 ~94,964 250 0.26
APR 2017–JULY 2019 ~114,943  ~111,166  293 0.26
APR 2017–DEC 2019
~142,855 ~159,317 433
0.27
APR 2017 - JUL 2020 ~167,684 ~235,630 666 0.28

a Numbers reported include only the post-marketing period and are inclusive of the whole month stated.

b The number of post-marketing patients exposed to ocrelizumab is based on estimated total number of vials sold, as well as US claims data.

c Based on reported fatalities in the Roche safety database in patients treated with ocrelizumab within the designated post-marketing period.

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.

*There are well-recognised limitations that should be considered when interpreting spontaneous post-marketing safety reports, including events may not be causally related to drug exposure; in the real-world setting, events are frequently confounded by factors such as multiple drug use and the presence of pre-existing comorbidities; reporting bias may exist for more significant outcomes, which may result in an overrepresentation of the more serious outcomes; and reporting rates can be stimulated by external factors such as press reports.

The causes of fatalities are recorded as reported to the company; while the company follows up on all reports to identify the cause, an exact diagnosis is not always possible. Some of the investigations remain ongoing and, therefore, the information may be subject to change.

CI=confidence interval; IFN=interferon; MS=multiple sclerosis; PY=patient-years; US=United States.

References
 
  1. Roche data on file; 
  2. Hauser SL, et al. Presented at MSVirtual2020 (8th Joint ACTRIMS-ECTRIMS Congress) (P0389);
  3. Leray E, et al. PLoS One. 2015;10(7):e0132033; 
  4. Goodin DS, et al. PLoS One. 2014;9(8):e105207; 
  5. Hauser SL, et al. N Engl J Med. 2017;376:221-234; 
  6. Montalban X, et al. N Engl J Med. 2017;376(3):209-220. doi: 10.1056/NEJMoa1606468.