Recent studies indicate that higher strength disease modifying therapies (DMTs) may slow disability progression in secondary progressive multiple sclerosis (MS), as well as reduce the number of relapses. There have also been trials in primary progressive MS but these, most notably using rituximab, were not clearly positive. For a more general review, please see the post Disease modifying therapies in multiple sclerosis.
The study being reviewed in this post, by Montalban et al., 2019 is on rituximab’s sister compound, ocrelizumab, and targets younger patients with more active disease, which seemed to be a subgroup that might have responded to rituximab.
There were 732 patients randomly assigned to ocrelizumab or placebo in a 2:1 ratio. Inclusion criteria were a diagnosis of primary progressive MS according to established criteria and age 18 to 55 years. Their disability had to range from moderate disability but still no walking impairment to impaired walking but able to walk 20m, perhaps with crutches (EDSS 3.0 to 6.5). The disease duration had to be within 10-15 years. They should never have had any relapses.
Pairs of ocrelizumab or placebo infusions were given every 24 weeks for at least five courses. The main end point was the % of patients with disability progression, defined as at least 1 point on the EDSS scale sustained for 12 weeks, or 0.5 points at the more disabled end of the scale.
Only if this primary end point was reached would the study be continued to test secondary end points such as 24 week sustained disability progression, timed walk at week 120, change in volume of MRI brain lesions, and change in quality of life on the SF36 score.
Patients had a mean disease duration of around 6 years, and 3% more patients having ocrelizumab had gadolinium enhancing lesions on MRI (27% versus 24%).
39.3% of placebo patients had increased disability sustained for a period of 12 weeks, and only 32.9% of ocrelizumab patients (p=0.03, relative risk reduction 24%). This was similar when confirming sustained disability over 24 weeks.
On the timed walk, there was a mean 39% slower performance after 120 weeks in patients on ocrelizumab and 55% slower in patients on placebo (p=0.04). There was no difference in quality of life (SF36 – physical component; a 0.7 out of 100 deterioration on ocrelizumab and 1.1 out of 100 on placebo).
There were three potentially relevant deaths in the ocrelizumab group (out of 486 patients), two from pneumonia and one from cancer, and none in the placebo group, but the overall rate of serious infections was not really different. Cancer rate was 2.3 % versus 0.8%, but obviously this would have to be monitored over further decades. Even during one year of open label extension there were two further cancers in the ocrelizumab group. The overall rate of neoplasms to date is 0.4% per 100 patient years, double the baseline rate, but this reflects a short time in a large number of patients.
In summary, a modest reduction in disability was seen on ocrelizumab, namely preserving against 0.5 to 1 point loss on the EDSS scale in 6 % of patients.
We focused mainly on the figure (see below) where it seems that ocrelizumab stopped about 5% of patients deteriorating in the first 12 to 24 weeks, from about 9% down to 4%, and then this difference was maintained throughout until the end of the trial where about 60% of patients still had not deteriorated. The plateau at 3-4 years is probably because of the end of the trial (see below), not a stable MS population.
The journal club were surprised at the focus on a 12 week primary end point. Patients would have progressed from zero to 3-6 out of 10 on the EDSS scale over a mean period of 6 years, yet they were measuring progression of 0.5 to 1 point over just three months. This is because there was some confusion over the phrase in the paper describing the primary end point as “percentage of patients with disability progression confirmed at 12 weeks”, and then in the results “percentage of patients with 12-week confirmed disability progression (primary end point) was 32.9% with ocrelizumab versus 39.3% with placebo.” It might seem that the primary end point was recorded at 12 weeks following treatment initiation. In fact the primary end point was recorded at the end of the study stopped after over 2 years when a prior defined proportion of patients had deteriorated. It means that over 2+ years, 32.9% of patients had a deterioration that was sustained over at least 12 weeks, i.e. not a relapse.
On the graph, it shows the numbers of patients remaining without disability at different times, starting at 487 and dropping to 462 at 12 weeks for ocrelizumab, which is 5.1% of patients and 244 to 232 for placebo which is 4.9%. Then at 24 weeks, this was 7.6% versus 13.1%. Some of the dropouts might be due to stopping from tolerability, but this was a small amount, possibly accounting from the small numbers of drop-outs between assessments every 12 weeks. For a 12 week confirmed disability progression, clearly there will be a lag in identifying patients whose increase in disability is sustained for 12 weeks. It seems that the time points do not add this 12 weeks because there is a first jump at 12 weeks in both groups. However, these numbers drop down to zero, not to the 60% of patients that appear not to have dropped out. This is likely to be because of patients dropping out because they started the study later and the study was terminated for them before 216 weeks. Nevertheless, factors such as drop outs due to tolerability and end of study probably explain the difference between the figures in the results and the plateau levels on the graphs.
What is interesting is that the difference between ocrelizumab and placebo diverged very early on the graph, and not really further over 2 years. While the 12-week sustained disability was designed to eliminate the possibility that the study is scoring relapses in previously primary progressive disease, or some other temporary factor such as injury from a fall or intercurrent infection, there is nevertheless a suspicion that ocrelizumab was mainly working well on a small subset with more active disease. The extra 3% with gadolinium enhanced lesions – a proportional difference of about 12% – unfortunately suggests a potential issue with randomisation; this might precisely be the group who could respond better.
It is noteworthy therefore that in its most recent NICE appraisal, the criteria for considering ocrelizumab are not those in this study, but a subset of primary progressive patients with enhancing disease on MRI imaging.
The journal club article described in this post was kindly presented by Dr Bina Patel, Specialist Registrar in Neurology.