Recently ProfG has been talking about immune reconsitution therapies and it has been asked if ocrelizumab is an IRT?
This is important to know because it says that you would not have to dose as frequently and whilst this may make a dint in the coffers of the manufacturer, it could mean an improvement in the risk:benefit profile for you…..if this is true.
No one wants an EMA or FDA investigation on side effects. Look at the problems with alemtuzumab if you don’t agree
ProfG seems to have been upsetting people by suggesting that if you deplete B cells for ever, it is not good news.
As a consequence he may have been knocked off the Roche Christmas card list, because of the suggestion that there could be infection risks from long-term B cell depletion risks. I am not on that list at the moment, but would not say no to a nice crimbo hamper:-). However, unless you buy into the “it is unknown” peddled by the Zombie science opinion leader brigade with the view that “if it hasn’t been shown it doesn’t exist”. This means that unless people all become “fungus mungus” then there is no problem. We know that serious infection risk is low, but it is not non-existant
I have to say “Come on people, think about it!” or simply just “think!”
Your immune system is there to protect you from infection, B cells are particularly good at getting rid of infections, get rid of B cells for ever and someone is going to suffer. It is not going to be the manufacturer. At the population level you will probably be OK, but if you are the unlucky individual, you will be unlucky.
I am sorry, but I don’t buy the alleged Ford Pinto approach to drug science. If you don’t get it. Watch “Class Action” . Maybe I will call it the “Astro Meridian” approach, in case Ford take the hump, about the way some companies appear to approach risk management. You are the car with the blinker problem, hopefully you won’t be hit when you are turning, but if you do, then you are literally in the hot seat. This makes me feel like Dr Pavel.
If ocreliziumab is an IRT you are being overdosed, but in reality even if it isn’t the case, the chances are you are still being overdosed. Why?
If we look at rituximab it is dosed every 6 months. It takes 8-12 months to replete CD19 B cells. Ocreliziumab is a more potent B cell depleter and it takes 15-18 months to replete, so why is it also given every 6 months?
Now if we look at the memory B cell depletion, this is maybe 15-24months (if you look at rituximab data) so with ocrelizumab would it be longer. We don’t know because there is no data. Shouldn’t we try and get it.
Now you can say the dosing schedule was selected when we didn’t know anything and I accept that. The Zombie opinion leaders will still say we don’t know anything. They go to ECTRIMS and teach the Status Quo.
You know me, I am not a fan of Status Quo. It all sounds the same:-).
If you accept that the memory B cell has any legs,then the six month dosing schedule is probably too frequent. The group from Genoa in Italy has data that support this. So you don’t have to be a Zombie. If you look at the time of memory B cell depletion with rituximab, it is more like 24.months. This suggests that following ocrelizumab they are gone for a long time. Maybe this gives a durable action for years. Is it IRT or long term immunosuppression.
My guess is it abit of both.
If you can extend the dosing schedule you perhaps do not keep you B cells out of existence and maybe, just maybe you can take a drug holiday, allow the drug to wash out, get pregnant, have a baby and still be protected. If this is true it is ADIOS to some of the competitors and the sales come rolling in.
Therefore, it makes sense to do these studies, just as it makes sense to do studies where you treat from onset and get the brain atrophy data that says alemtuzumab is not special, the important aspect is to ge on effective treatment early. maybe you show it is special, but the cladribine data from ORACLE suggests otherwise.
Any way what is this post all about?
It is about the study from Sweden. It reports on the effect of stopping rituximab and waiting …from 7 months to 8 years. There were 6 cases of disease activity from 92 people. To me this seems like rituximab is indeed an IRT, just as I said it was 2 years ago, as it seems to be alemtuzumab-like.
It’s not surprising if they work the same way. Unfortunately, there are some people who don’t buy this simplistic view as it makes it all too easy, especially when you sell the unknown, unkown idea. The companies and their opinion leaders want you to think each agent has a special mechanism of action. Do they really?
The study with ocrelizumab is happening as people run out of money and have to stop ocrelizumab. I say come on be brave, Do the trial and show this to be the case, as we need to know that this approach is safe. I’m sure profG and the Gang would love to do the trial.
Go on send a christmas card and give us that present of the ADIOS trial..you and I know it makes sense, let’s not wait to be hit whilst turning right, whilst flashing! After all no one wants to be caught with their pants round their ankles:-)
Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity. Juto A, Fink K, Al Nimer F, Piehl F. Mult Scler Relat Disord. 2019 Oct 24;37:101468.
BACKGROUND: Rituximab (RTX) and other anti-CD20 therapies are increasingly used as disease modifying treatments (DMTs) in MS. However, data on reasons to interrupt treatment, alternative DMTs after anti-CD20 therapy and potential rebound disease activity are limited. The objective here was therefore to determine the rate and cause of RTX treatment interruptions and responses to subsequent DMTs in a large single centre cohort addressing also the hypothesis that there would not be rebound activity after discontinuation of RTX, regardless of reason for discontinuation and irrespective of subsequent treatments.
METHODS: A retrospective observational study of all relapsing-remitting MS (RRMS) patients having received at least one dose of RTX at the Karolinska University Hospital from 2009 to 2018 and having either stopped treatment or had more than one year since last RTX infusion, as identified in the Swedish MS registry with additional data derived from clinical charts.
RESULTS: As of February 2018, we identified 808 patients ever treated with RTX out of 1513 RRMS patients with current or previous DMT, 92 (11%) had terminated RTX; 27 (29%) stopped RTX due to pregnancy, 26 (28%) due to adverse events, 23 (25%) for other reasons, 9 (10%) due to stable disease and the remaining 7 (8%) due to lack of effect. The cohort of 92 patients was followed until April 2019, when 34 had restarted RTX, 27 switched DMT, 24 remained without DMT and 7 were lost to follow up. Of the 7 patients terminating RTX due to lack of effect, 4 started ofatumumab, 2 had autologous hematopoietic stem cell transplantation and 1 was lost to follow up. In all of the 92 patients, after initial RTX discontinuation, only 3 patients had relapses and 4 had new T2 lesions (one of which had both). Gadolinium was administered in 78% of follow up magnetic resonance imaging (MRI) with no enhancing lesions found (mean MRI follow up from RTX discontinuation 29 months, range 7-92 months, n = =77).
CONCLUSION:Findings are consistent with a low rate of RTX interruptions, with pregnancy and adverse events as most frequent reasons. A small proportion of patients switched due to breakthrough disease in context of incomplete B-lymphocyte depletion. Signs of ongoing disease activity in the remaining group was low regardless of whether a new DMT was started. These findings are consistent with a long acting effect of RTX in RRMS and absence of rebound disease activity phenomena upon stopping therapy.