Open [Tokyo, Japan] Study of the Efficacy and Safety for Rituximab in Myalgia Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

[Jaybee00]

BTW I emailed the Japanese PIs a while ago to express my concerns about their trial, but of course never heard back.

Also now Nancy Klimas wants to do a rituximab trial on the “auto immune subset”

"What's Up, Doc?" Nancy Klimas on Viruses, ME/CFS's Greatest Need, and Her ME/CFS Clinical Trial - Health Rising

Dr. Nancy Klimas says what's exciting her most right now in the ME/CFS field is a renewed focus on herpesvirus reactivation and what artificial intelligence will bring.

www.healthrising.org

 

[Utsikt]

Also now Nancy Klimas wants to do a rituximab trial on the “auto immune subset”

Based on what a computer model said about how to «knock down» EBV with a combo of ritux and a herpes antiviral.

Maybe we should start by establishing if EBV actually is a problem?

 

[Jonathan Edwards]

Also now Nancy Klimas wants to do a rituximab trial on the “auto immune subset”

That really is a bizarre et of statements reported by Cort Johnson. Including a suggestion that Travis Craddock studied EBV in B cells and epithelium. I know Travis well and he is a mathematician involved in computer modelling, not an immunologist. I don't know where the strange statements actually arise from but this makes no sense.

If people have viral reactivation the last thing you want to do is give them rituximab - they are likely to die. Unless of course the problem really is EBV, but we have pretty extensive negative data on that.

 

[V.R.T.]

BTW I emailed the Japanese PIs a while ago to express my concerns about their trial, but of course never heard back.

Also now Nancy Klimas wants to do a rituximab trial on the “auto immune subset”

"What's Up, Doc?" Nancy Klimas on Viruses, ME/CFS's Greatest Need, and Her ME/CFS Clinical Trial - Health Rising

Dr. Nancy Klimas says what's exciting her most right now in the ME/CFS field is a renewed focus on herpesvirus reactivation and what artificial intelligence will bring.

www.healthrising.org

Her trial that is designed to cure ME/CFS that is apparently underway according to this article sounds utterly bizarre. I mean I'd love if it were to work but...

 

[V.R.T.]

All those arguments might be relevant if we have reason to think that targeting B cells make sense in the first place. With major risks involved I find it hard to see how any of these approaches are justified at present.

You seem to have changed your tune somewhat on dara's possible efficacy, which iirc is anti cd38. Are you still sceptical of the cd19/20 drugs like those Schibenbogen is trying?

 

[Jonathan Edwards]

You seem to have changed your tune somewhat on dara's possible efficacy, which iirc is anti cd38. Are you still sceptical of the cd19/20 drugs like those Schibenbogen is trying?

I have shifted to thinking that there may be a coherent rationale for targeting plasma cells. But we still have pretty good evidence for targeting B cells being useless - which would include CD19/CD20 based approaches. But even for Daratumumab I have said that it may be a useful experiment that may even prove clinically worthwhile for some people but that I think it is pretty unlikely to be a viable treatment in the longer term and will have significant risks.

 

[V.R.T.]

I have said that it may be a useful experiment that may even prove clinically worthwhile for some people but that I think it is pretty unlikely to be a viable treatment in the longer term and will have significant risks.

So you think it might lose efficacy with repeated doses? Or is it just that the risks are too high?

On a related note are the risks immunosuppresion? I know cyclo had a lot of risks but not as au fait with daras

 

[Jonathan Edwards]

So you think it might lose efficacy with repeated doses? Or is it just that the risks are too high?

On a related note are the risks immunosuppresion? I know cyclo had a lot of risks but not as au fait with daras

Mostly the long term risk of keeping someone hypogammaglobulinaemic. I don't think we know that much about long term risks of Dara but they are most likely to relate to low Ig levels.

 

[ME/CFS Science Blog]

There's some more info about this trial in the presentation by Dr Sato during the Berlin conference:


Here are some slides:

 

[ME/CFS Science Blog]

I heard people suggest that the dosage might be different (and that the Norwegian trial couldn't provide the dosage because of lack of funding). Not sure if this is true. Here's what I could find online:

Fluge et al. 2011 (pilot RCT, n=30)
Rituximab 500 mg/m2 given twice two weeks apart, with follow-up for 12 months

Fluge et al. 2015 (phase-2, open-label, n= 29)
2 infusions (500 mg/m2) 2 weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months

Fluge et al. 2019 (phase-3, RCT, n = 152)
2 infusions of rituximab (500 mg/m2 of body surface area), 2 weeks apart
followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months

Japanese trial (RCT, crossover, n = 30)
four times at weekly intervals during the first three weeks of the primary and secondary evaluation periods.
(375 mg/m^2/week iv. x 4 times)

Not sure if this is a significant difference.

 

[Utsikt]

Fluge et al. 2015 (phase-2, open-label, n= 29)
2 infusions (500 mg/m2) 2 weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months

Fluge et al. 2019 (phase-3, RCT, n = 152)
2 infusions of rituximab (500 mg/m2 of body surface area), 2 weeks apart
followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months

So the only difference between P2 and P3 was the timing of the later maintenance doses, and possible the maintenance dose (500 mg in P3 vs 500 mg/m2 in P2)?

 

[ME/CFS Science Blog]

Yes I think so. Perhaps others can double-check.

 

[ME/CFS Science Blog]

the maintenance dose (500 mg in P3 vs 500 mg/m2 in P2)?

This is mentioned here in this documentary (38:20):


Scheibenbogen later commented on this:

Scheibenbogen proposed that the reduction of the maintenance dose in the Phase III trial, though, may have doomed the trial. The Phase II trial used maintenance infusions at the rate of 500 mg/m2 (maximum 1,000 mg) at 3, 6, 10, and 15 months follow-up. The Phase III trial used a fixed dose of 500 mg at 3, 6, 9, and 12 months. Scheibenbogen reported the fixed-dose used was caused by financial problems.

Scheibenbogen called the maintenance dose “critical” and questioned whether it was too small in the Phase III study to knock the B-cells down

"Emerging Options for Autoimmune ME/CFS": Scheibenbogen at the 2021 IACFS/ME Conference - Health Rising

Several facets of chronic fatigue syndrome (ME/CFS) suggest it may have an autoimmune component including it's infectious onset, autoimmunity in families, research findings, and the results of small clinical trials.

www.healthrising.org

 

[Utsikt]

This is mentioned here in this documentary (38:20):

Thank you for finding that.

@Jonathan Edwards do you have any thoughts on the importance of the size of the maintenance doses for Ritux?

Do we know how it works for other applications for Ritux?

 

[Jonathan Edwards]

I think it inconceivable that the lower maintenance dose was the reason why phase III failed. From my experience it was easily adequate. You can halve the dose of rituximab and not get much difference in efficacy.

Remember that the Phase II trial also had a negative result. SO we are not looking for an explanation why one trial succeeded and another did not. In the open label part of phase II it looked as if there were responses but the blinded part showed no credible pharmacodynamic uniformity. I encouraged Fluge and Mella to do a phase III because the original primary outcome measure for phase II was arguably badly planned. But the apparent positive result at six months could easily have been a chance finding and the pharmacodynamics did not provide any supportive evidence.