Once this surfaces on a site like Pubmed…Person A (alias) and others will be saying…….what the F***. “That scumbucket MD has published my data!”.
Yep that’s true we have. It’s a lot easier than doing experiments, isn’t it!
However, I guess most famous neuros like Person A know the feeling. Others do the work and are not mentioned in the spotlight and the famous neuro’s name goes on the front :-). It’s good to have a bit of role reversal every now and then so you know both sides of the equation. Why is this done? Because it is a seal of approval etc
Indeed, some time ago ProfC in this case, that is Prof Coles from Cambridge posted a paper criticising the top Docs for sitting on the coat tails of Pharma and publishing a disproportionate amount of clinical trial reports. However, think of the positive. We have just saved pharma a wodge of cash as now they don’t have to pay a medical writer/employee to write-up the study. Yep I feel guilty, but it has been 10 years since the work was first reported.
When ProfC published this paper. Authorship of phase 3 trials in multiple sclerosis.Coles A. Ann Neurol. 2018 Apr;83(4):653-655. doi: 10.1002/ana.2520 Some of the Top Docs were outraged, some didn’t get it that ProfC was having a dig:-(. We still have to work out was ProfG…..Person C or D, E or even ironically maybe PersonG. We all know who Person A was…you would have to be Cuckoo not to know which Country they came from, or at least work in.
The subtext of paper by ProfC was that persons A-Y had become the puppet mouthpieces for the pharma machine, which gets medical writers to produce reports so that they conform to the law and ensure that they are dull as dishwater. So we have the structure (A) Demographics (B) Efficacy (C) Side effects (D) Dull.. because there is no interpretation. However, ProfG will argue that they play an important part in the trial design and I am sure that is true. But when we see the corporate Poster and platform Presentations we really know who is designing the content that you get to see. I am sure ProfC has been the recipient of this treatment too.
I will take abit of stick for this one…..as I have broken a rule, but as you know I was never a fan of Status Quo. However, is this a new opportunity… Snooze and you lose…..to encourage early publication.
Anyway, Person A reported this phase II study in 2012 (we got the poster) and a different person (we got the slides) reported the same stuff in 2013 indicating that pharma was in control because if it really was your work somebody else from a different lab would not be presenting it…Would they?…. So Pharma decides when to publish…They decided not. I think because the message was not something they wanted other people to hear and some of the later points were, I must admit, a bit data-lite and based on few observations and so have to be viewed cautiously.
There was no interest in reporting the study. That was until 2017 when we started to ask for the data of the trial extension because the sponsor of the trial had signed up to clinicaltrialdatarequest.com. During this time we were told that the trial data was available. However we had stirred something, and it wasn’t in my trousers:-). We were told that it was going to be published…So we backed off and gave Person A time to publish it. However, we made a formal request to clinictrialdatarequest.com. We extracted the data from the meetings reports and got the paper ready.
However, COVID-19 came along and we said times up, we so deposited on MedRXiv (14 January 2020) so it was visible and as we had got the nod that we could have access to the data, we put the paper in the public domain before we signed any of the legals with the sponsor. The plan was to get all the data out and then fill in missing bits.
Then the ABN came out (Mid March) and said delay ocrelizumab and at that point we still hadn’t seen any data and thought it was time to get it out as neuros weren’t reading pre-print sites. We went to editor of MSARDs and asked for a quick turn around, they said yes and the paper was submitted and then the plans went proper “tits-up”, and it has just surfaced because the speedy review was done at snail pace. Are we sure one referee in particular was not on the pay role of the sponsor:-(. However, by the time the paper surfaced we knew that COVID-19 was not an issue. Just before the re-review, we got access to the trial data. It is inside a virtual portal were you can’t copy anything and the files were coded but we weren’t given a key to know what was what. We are in lock down and trying to work on a few hundred thousand line spread sheet in a programme I have never used before on a 20cm lap top screen. It wasn’t going to happen quickly
So what does the data suggest? well yit says you are probably OK to delay infusion of ocrelizumab for a few months and disease should be held at bay for most people. I think this is good to hear. However in saying that it also says that dosing every 6 months may be over-kill and that you could reduce the frequency of dosing to get the same effect. I put the proviso here is that this may in part depend on how big you are. If you are petite the effect of the drugs may last longer. So the difference between the fastest to slowest repopulator was 27-175weeks (6 months to three and a quarter years so if you are that later person you have had 5-6 cycles of drug when there may have been no B cells to deplete. Perhaps you could have a drug-free pregnancy. We say do the study and show if this is true on not, do the ADIOS trial. If you don’t someone will
The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.
David Baker, Gareth Pryce, Louisa K. James, Monica Marta, Klaus
Schmierer Mult scler Rel Dis 2020. https://doi.org/10.1016/j.msard.2020.102279 (Free copy here)
- Ocrelizumab phase II trial extension data has 18-month post-drug follow-up.
- Annualized relapse rate seems to remains low during the drug-free follow-up.
- Infections and adverse events seem to be reduced during drug-free follow-up
- Extended interval dosing may be possible that maintains efficacy and allows for more successful vaccination to new infections
- Extended interval dosing may afford a drug-free pregnancy
- Formal trials to demonstrate the benefit of extended interval dosing are warranted
Objective: Ocrelizumab inhibits relapsing multiple sclerosis when administered every six months. Based on potential similar memory B cell depletion mechanisms with cladribine and alemtuzumab, we hypothesised that CD20-depletion of B cells by ocrelizumab may exhibit a
duration of response exceeding the current licenced treatment interval.
Methods: Internet-located information from regulatory submissions and meeting reports relating to the unpublished open-label, phase II ocrelizumab extension trial (NCT00676715) were reviewed. This followed people (54-55/arm) with MS, who switched from placebo or interferonbeta
to ocrelizumab for three 600mg treatment cycles (week 24, 48, 72) or people treated with ocrelizumab for four 600mg treatment cycles (week 0-72), followed by an 18 month treatment free period.
Results: CD19+ B cells were rapidly depleted within 2 weeks and slow CD19+ B cell repopulation began about 6 months after the last infusion with median-repletion of over 15 months. The reduced annualized relapse rate during the published efficacy study appeared to be maintained in
the extension study and there were no new T1 gadolinium-enhancing or T2 lesions detected in the treatment-free period. Importantly, within these extension cohorts, there appeared to be fewer adverse events and infections events.
Conclusions: Ocrelizumab appears to induce durable relapsing disease inhibition, within 3 treatment cycles, Therefore, it may be possible to reduce the frequency of dosing to maintain efficacy, whilst limiting infection and other risks associated with continuous immunosuppression and could allow more effective vaccination against new pathogens. Further studies are now clearly required to determine whether this data is robust, as few people seemed to complete the study.
UPDATE YOu asked does thismean you have to have 3 infusions for this to occur. The answer isprobably no. The reasonI talked about 3-4 doses is because that was in the trial Iwas reported. If you want to know about one dose we can get an idea from a paper in arthritis https://pubmed.ncbi.nlm.nih.gov/18759293/
The dose used in MS is 2 x 300mg. So between the green triangle and the blue circle, so you can see that there was still marked depletion at 72 weeks. You can also see the 2 x 10mg dose depleted . 80 B cells per ul is the lowerlimit of normal and you can see a 6 months over 80% of people have notgot to this level to 1 year about 40% of people have got to half of lower limit of normal. The study is problematic as people on arthrits treatment get methotrexate also
It also makes a difference how big you are if you weight less than 60 kg youwill bea slow repopulator and if you are over 90Kg you will be a quick repopulator
Source FDA CENTER FOR DRUG EVALUATION AND
RESEARCH APPLICATION NUMBER: 761053Orig1s000
Small people get more drug on board and deplete better
COI: Multiple but not considered relevant. ProfG was not party to this, as he was conflicted…but shows we don’t all think alike. However on issues of safety, I am sure he will say publish and be damned..and I am sure I’ll be burned in Hell for doing this.
Update Thanks for the link https://www.msdiscovery.org/ms-galaxy ProfG in Yellow. So it is easy to see who person A and B and C are. Now I understand why the paper relating to Alemtuzumab part V was diluted from the original message.