There are many that would not contemplate this view.
What do you think?
Rituximab is a CD20 depleting antibody that was originally developed for B cell cancers. Many years ago it was shown that rheumatoid arthritis responded well to deppletion of CD19 and it was only a matter of time before neurologists copied the arthologists and put it into MS. Prof Huser took up the challenge, being a stones throw from Genetech who made the antibody by creating a chimeric antibody of mouse monoclonal antibody against human CD20 and having human antibody tail.
So we have three papers
Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis – Commentary.Cree BA. Mult Scler. 2018 Feb 1:1352458518760717.
Should lower cost alternate medications with comparable mechanisms of action, but without the proof from registration studies, be used in lieu of branded medications with proved efficacy and safety?
Professors Piehl and Hillert argue that comparative effectiveness studies support use of rituximab as a MS disease modifying treatment (DMT), and that possible differences in association with malignancies found for ocrelizumab, but not associated with rituximab, make rituximab a better option
Professor Wallin takes the opposing view that ocrelizumab offers an advantage over rituximab with regard to proof of efficacy and patient access
Prof Cree thinks the argument to favor rituximab (or other lower cost offlabel medications) is economic
- Most third party payers do not authorize off-label variant
- Prescribing clinicians inevitably favor approved, accessible medications.
The US taxpayer has been funding institutions (NIH) has had little interest in promoting development of lower cost treatments that compete with branded medications over medications that effort
So what was said.
“Three anti- CD20 targeting monoclonal antibodies have been tested in multiple sclerosis (MS); rituximab (mouse chimeric), ocrelizumab (humanized), and ofatumumab (fully human) and work”.
Actually there are a few more, so safe ground to say that B cell depleting therapy is beneficial for controlling relapse.
The tack is to base the argument on medical arguments leaving the legal and cost issues aside. However, surely cost and the legal is the real battle ground as we know rituximab can work.
But for Prof Piehl the battle group is efficacy, immunogenicity and safety.
MT Wallin says “No”
It is argued that the antibodies are not the same.
Yes we know about the price but what about the biology?
It is argued “The choice of RTX or OCR should be based on efficacy and safety issues. Although costlier than RTX, it can be argued that OCR is a more effective B cell–depleting agent with the potential for a greater likelihood of stabilizing MS activity in the right patient”.
1. Not as good.
It is argued by the No camp that that “Both mAbs differ in the mechanism for depleting B cells. OCR has a higher capacity for antibody-dependent cellular cytotoxicity and weaker complement-dependent cytotoxicity compared with RTX. OCR, thereby, provides a more direct path for eliminating B cells which could make OCR a more effective agent with less untoward effects on the immune system”.
Is this however true?
The yes camp made a case that rituximab works.
It stops the rebound associated with discontinuation of natalizumab.
It stops relapse, etc.
A case that one was better than the other was not really effectively made by the No camp.
Yes it did better in PPMS, but if you did a trial in PPMS knowing the result of the ocrelizumab trial would you be able to get the same result
3. Immunogenicity. Infusion reactions and upper respiratory infections are the most common untoward effects overall for both RTX and OCR.
The no camp says there is greater immunogenicity with rituximab, the yes-camp accept this and say it occurs in 25% of people.
“There was a significant association between presence and titers of ADA (Anti drug antibodies), and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level.
However it is at the individual level we we see the effect
“With regard to ocrelizumab, anti-drug-binding antibodies were found in 0.4% and 1.9% “
Yes we would expect that. This is a problem if you have to give rituximab forever, but do you have to do that?
Maybe not if it has induction therapy potential.
Is one safer than the other?
I think the case was not really made in the No-camp and the debater may have killed his cause talking about Breast cancer with ocrelizumab.
Is the breast cancer signal real? Should have been the question addressed.
If one is more effective, then it could be less safe as the mechanism for control autoimmunity and infection would be the same. You can’t have it both ways
Indeed Prof Piehl makes the argument that
“The development program for ocrelizumab in rheumatoid arthritis (RA) was been terminated and a negative safety signal for serious infections was evident” and make the argument for cancer as an issue.
Prof Piehl has a few mentioned a few including links with Roche. However, there was no mention of a big grant from PCORI to test rituximab in MS…maybe not a financial conflict but in the case of the debate clearly an academic conflict as the surely Prof Piehl is passionate that they are doing the right thing.
Prof Wallin one the other hand had no relevant conflicts suggesting that Pharma have not used his services in this area, and so the pharma side of the argument was not really made. So the debate is perhaps not coming from a place of passion. You need someone willing to give the pharma perspective, but most people would not want their neck to be put on the block.
However, there is more to the story that efficacy and safety and where did rituximab come from in the first place…yes pharma innovation….yep using academic knowledge.
Maybe we could do another debate
DrK. Subcutaneous cladribine (Litak) is an acceptable alternative to oral Cladribine (Mavenclad) for treating multiple sclerosis- Yes
Yep we have this debate going on since 2012 within the lab, it is a relevant debate to be had. We should also have as you know where the holes in your argument lie.
ProfG. Subcutaneous cladribine (Litak) is an acceptable alternative to oral Cladribine (Mavenclad) for treating multiple sclerosis- Yes
However, you could you argue for
(a) Price of Innovation.
(b) Society benefits from a healthy pharma industry
(c) People with MS benefit from a healthy pharma industry
(d) Pharma involvement has educated lots of neurologists in
MS leading to better Care
(e) Pharma involvement has put MS nurses, centre stage
(f) etc, etc, etc
What stance would ProfG argue on
Whats more we could even do
But have you asked How much is it to do an MS trial and how much does it cost to do a psoriasis trial?
Is it eleven times more?