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.