Battle of the CD20-depleters….One is better than the others…Really?…..Read on

B

I was thinking that if you are going to do head to head studies between rituximab and a current drug….it should not be against dimethyl fumarate, tecfidera, interferons etc as this is like putting me up against Usaine Bolt in a 200m sprint. You know who if going to win.

Surely it would be better to put rituximab against ocrelizumab, which are both administered every 6 months…However, if you try and show one is superior to the other in terms of efficacy I suspect you need a large number of people in a trial, this costs too much for most non-pharmafunders. Likewise you need large expensive studies to show agents are not inferior.

Now you may say why compare rituximab to ocrelizumab when rituximab is not approved….maybe it should be ocrelizumab against ofatumumab.

Who would pay for a trial as it is dangerous to do studies against agents where you may loose and ruin your asset.

However perhaps you could simulate a contest from available trial data.

This was done here The highlights are:.

Two newer MS therapies were compared using simulated treatment comparisons.

ASCLEPIOS I/II patient-level data were used to adjust for cross-trial differences.

Ofatumumab significantly lowered the annualized relapse rate versus ocrelizumab.

So this says ofatumumab is better…..it may well be as people may like to dose at home rather than pop into hospital to get an infusion. The paper says…………………………………………………….

Samjoo IA, Klotz L, Giovannoni G, Drudge C, Haltner A, Worthington E, Zhao M, Brennan R, Häring DA, Cameron C, Adlard N. Simulated treatment comparison of efficacy outcomes for ofatumumab in ASCLEPIOS I/II versus ocrelizumab in OPERA I/II for the treatment of patients with relapsing multiple sclerosis. Mult Scler Relat Disord. 2022;66:104031. doi: 10.1016/j.msard.2022.104031. PMID: 35841716

Background: Ofatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab.

Methods: Given the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change).

Results: Although comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57-1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47-1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43-0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes.

Conclusion: Ofatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.

So the first question I think & thought of before I read the paper is/was (a) Who funded the study. This helps you to assess independence. Second is (b) What is the biological difference between the agents that could explain a difference between agents?

To the answer to the first question.

It is the manufacturer of ofatumumab and is witten by authors working for a company that seems to specialise in commercialisation of products, who are paid by the manufacturer of ofatumumab….Em so independence is out of the window and so you just have to bear this in mind, because would the manufacturers of one drug pay to say their competitor is better. Yep Turkies don’t vote for Christmas

In the study they didn’t find any difference in rates of progression but they did report differences in effects on relapse rates and it appeared that there were about 20-40% few relapses. However, there was no indication that a protocol and a pre-defined plan was followed so you could trawl through the data to see what is different and then report it.

However, the relapse rate may have been on their mind because:

If we look at the trials the Annualized relapse rate with ocrelizumab was 0.16 (OPERA I & II. Hauser et al. 2017) and ofatumumab was 0.11 (ASLEPIOS) and ASLEPIOS (0.10. Hauser et al. 2020) so a cigarette packet calculation and difference in relapse rates is about 30% better……….Is this data hacking to find benefit?

There is a saying is “Time Heals” and I can prove it because if we look at the relapse rate of interferon beta-1a three times a week in the OPERA I/II trials it is about 0.29 (Hauser et al. 2017). However, it was between 0.39-0.52 in 2012 (Cohen et al. 2012/Coles et al. 2012) CARE-MSI&II), but if we look at the early beta interferon trials (PRISMS. Ebers et al. 1998) there were was 1.73 relapses per patient. I guess in a in two year study….so rate 0.87 per year which is about 66% better in 2017….There you go Time Heals.

However, you will say “Hang on a minute these trials were done over 20 years apart and there are bound to be differences, even subtle differences, in the people in the trials”. I would say you are right, you shouldn’t compare Chalk with Cheese….You could argue that in this current study people were matched, but is that Cheddar Cheese with Swiss Cheese or Goats Cheese?

There have been studies saying that ocrelizumab and ofatumumab are similar (Samjoo et al. 2020 https://doi.org/10.2217/cer-2020-0122 . The authors accept there may be bias in their analysis.

However, the answer to the second question…There is no answer given….They both wipe out CD20+ B cells and once depleted they are depleted with both agents…is one better at destroying B cells than the other?

The only way to know if there are differences are to put people into a trial and randomize them to either ocrelizumab or ofatumumab (or let’s go the whole hog and put rituximab in the mix) and let’s see if there is a big difference….There may well be…..but shouldnt we prove it?. If there is such a big difference it should be easy to find. Will the study get done or has a message seed been sown in people’s minds?

Or has the seed been sown and ocrelizumab is not going to get a chance.

COI: Blah, Blah, Blah, Blah, Blah but buried somewhere in the list, I should mention the manufacturer of ofatumumab…but not related anything about ofatumumab. However by commenting on the post am I simply a pawn in the publicity machine or ProfG’s evil twin spreading a message…You decide

Disclaimer: These are the views of the authour…it is an opinion and only that.

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MouseDoctor

16 comments

  • “Who funded the study?”

    “It is the manufacturer of ofatumumab and is witten by authors working for a company that seems to specialise in commercialisation of products, who are paid by the manufacturer of ofatumumab.”

    Any idea how much the authors would get for working on this study? Are we talking hundred of pounds or thousands? I find it a bit galling that medics moan about the intense pressure they face working for healthcare organisations such as the NHS, yet find time to work on these extra curricular paid jobs. You often see 10-15 companies listed on the COI page of presentations. If the medic gets £5,000 – £10,000 a year for each company they work for you could be looking at an additional income of £50,000 – £150,000 a year. No wonder med schools are over subscribed. I suspect that some neuros could be on £500k a year – NHS salary + private work + work for pharma companies. Nice work if you can get it bearing in mind that no MSer is cured!

    • I suspect thousands to the company doing the promotion as they are doing a job….as for the advisors, its depends on what you do and how long it takes and who you are as there will be different re-imbursements for different positions and there is the taxman. In the states the costs associated with each advisor is recorded….however bear in mind that there costs are not how much some people may be paid as this includes their airfares, hotels, transport, food etc but some surgeons make a real packet…In UK it is voluntary at present…I do a critique of a paper which is on an animal study that implies that drugs needs to be repeatedly given…I then show the students that the authors had had $250,000 from the manufacturer attributed to them….however people get paid for work and there are going rates….how many footballers get £200,000 a week for 3hours work and don’t win any trophies….I dont think that most people do it for the money

  • “Data-fracking is the fracturing of a data set by the application of a pressurized search through as many data points as is necessary to find one that has the appearance of being positive. Typically, data is combined with cortisol and caffeine, and the mixture is injected at high pressure into statistical analyses to illuminate illusory correlations along which the appearance of success may migrate to a press release. The products of data-fracking tend to be more gaseous than substantive.”

    • I will find out soon as I am meeting them today but they don’t have my telephone number:-) but have my email. However what has been pointed out here is look at COI…..that is why they are there. Science papers rarely have people discussing COI because they don’t believe there is a conflict but as pharma is a business there are rules. However COI are there to be looked at ….. as ProfG says the COI help you to decide if you take or leave such information however I believe that he is happy that things are correct and my saying that if effects are so marked a head to head trial is warranted..As a community this should get done because if there is benefit we should know about it. It doesn’t say the findings are wrong. I am sure you could make the case that monthly dosing is better than 6 monthly dosing as some people will repopulate before 6 months and so slip through the cracks, you could make the argument for less ADA human verses humanised etc.

    • I am happy to receive complaints and will modify my thoughts, amend retract, apologise etc.
      Maybe I need to stop posting…

  • Saying what you think based on your fundamental understand of the DMTs mechanisms is nothing to apologize for. Medical trials are obviously tainted by big pharma since the studies are oriented towards medical success, but also financial gain… sometimes these are conflicting objectives.
    It is the way a capitalist socially works and it’s not going away, but, the readers should be aware of this. Bringing awareness to the issue is a sign of a good scientist and researcher

  • Have you seen this article about fabricated data in a landmark 2006 study describing the underpinnings of Alzheimer’s.

    Allegations of fabricated research undermine key Alzheimer’s theory https://www.nbcnews.com/science/science-news/alzheimers-theory-undermined-accusations-fabricated-research-rcna39843

    Where were the peer review gatekeepers?!? Were they motivated by profits? Were they just blind?

    Can’t get a B-cell centric study on MS published, but fabricating data for Alzheimer’s is acceptable?!? Shame on the original author, glad someone cared to take a second look.

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