Rituximab study in norway. An application to The Research Council of Norway

[Nielk]

@deleder2k -

Best of luck to you. I know that you are familiar with my experience so far with Rituximab. It is still early on for me but, so far, I have had no side effects from the Rituximab except slight reaction at infusion time which was quickly dealt with. (Dr, Edwards said that it wasn't even a reaction but normal)

I had some side effects to a drug which was started for me at the same time - Methotrexate, which has been discontinued.

I feel confident with my doctor and hospital that they can deal with any possible complications. I am sure that you will be in good hands there in Norway as well.

This is really a decision that only you can make for yourself. You sound very knowledgeable and intelligent. I understand that in your case it is different than mine in that you do not know whether you will be given Rituximab or a placebo. That is something that you need (and I see you are) taking into account.

As far as my ME symptoms so far, they have no gotten worse. I am sure that that everyone is different.

My best to you.

 

[Jonathan Edwards]

@deleder2k
@Jonathan Edwards, is it possible that the preliminary work being done for the UK Rituximab trial would advance the search for a reliable marker for the disease, which might help stimulate research and medical activity, or is its aim solely to try to stratify patients into responders and non-responders for Rituximab treatment?

I have not been keeping up with this thread, as people have noticed. I will try to catch up. The UK work is definitely being done with the aim of trying to pin down a marker. Like the Norwegians we want to keep as wide angle a view on inquiry as we can. I am not in a position to give details but we already have a network of people contributing to collaborative ideas, some of which have already led to experiments being done. Dr Bansal has been looking for autoantibodies, separately from the trial plans, and there are hopes for further collaboration in that direction.

Some people have asked why we need another trial on top of the Norwegian study about to start. I have talked about that under the thread with my name on it but can recap here. For me it is largely as a way of being scientifically rigorous in terms of repeating results on different populations in different labs, but also about trying to address the problem from a slightly different angle to get at some of the back ground issues as above. It is not clear to me exactly what would be needed to persuade regulatory authorities to approve the treatment but it is probably not even clear to them at this stage so my thought is just to do the most rigorous science we can and hope that shows through. There is also the simple point that we may be able to offer some people some useful treatment at this stage rather than wait for the Norwegian study to report in about two years time. Perhaps the most important thing is that we have new teams actually thinking about ME research on a daily basis and setting up collaborations.

 

[Jonathan Edwards]

@Jonathan Edwards -- Apologies if this is something you've already covered on these forums somewhere. What are your thoughts on the size of the therapeutic effect that patients experienced in the Norway RCT published in 2011? I know that 60% of Rituximab patients were "major responders" as the researchers defined the term. But digging deeper into the data, it looks like only a couple patients had at least one eight-week period where their average self-reported fatigue score was a 5 ("moderate improvement") or higher. A large % of patients had slight improvement for a significant period of time, but very few had even moderate improvement for a significant period of time, let alone major improvement. To me, it looks like the results do indicate that Rituximab is having a statistically significant effect, which would definitely move the science forward, but it doesn't seem like the effect is large enough to make a big difference in the patients' lives. Obviously, if future trials replicate these results, it would still be extremely valuable in terms of figuring out what's going on in CFS, but maybe less valuable in terms of validating Rituximab as an effective treatment.

I guess my question is this: Do you think that adding maintenance doses as was done in the subsequent open-label trial -- at 3, 6, 10 & 15 months -- could not only increase the duration of the effect, as has been discussed, but also possibly increase the size of the effect?

Thanks a ton in advance.

This is a good question and so far I am not in a position to give a first hand informed opinion so may not be able to say much more than you. However, I do think that real impact on people's lives may be much greater once an optimal continuing dosage schedule has been arrived at.

 

[Jonathan Edwards]

@Jonathan Edwards, Do you have a theory why gamma globulin works for many patients? Unofficially a doctor named dr. Mette Johnsgaard at the Balder clinic in Oslo have 60 patients on 5ml Gammanorm weekly. All with ME defined by Canadian criterias. 50% of them are significantly better. I also heard dr. Mella speak in Stockholm, and he explained that they gave gamma globulin infusions to a patient that was so sick he/she couldn't get in to the hospital for Rituximab treatment. They gave the patient one single treatment with gamma globulin, and it helped a lot. If I am correct gamma globulin strengths the immune system, while Rituximab breaks it down.
Why is it that it could work? and is there any reasons that one shouldn't try it?

The apparent benefits of gamma globulin have always been mysterious. Gamma globulin is, roughly, synonymous with immunolglobulin, IgG or antibody. Gammaglobulin treatment is more or less giving 'an average mixture of lots of other normal people's antibodies'. One idea is that if you give extra antibody the immune system turns down its own rate of production, which may include 'bad' antibodies. The evidence for this is not very convincing and nobody has found a feedback control loop that works like that. Another idea is that the antibodies from other people in combination with your own antibodies and maybe other things form complexes (effectively the other people's antibodies argue with your own antibodis) and the immune system is so busy dealing with these complexes that it forgets to damage your own tissues. There is actually some reasonable support for this but it has always seemed to me a bit cockeyed and not something that would last very long. Another possibility is that if your antibody producing cells have got into a loop driven by the bad antibodies they make then shifting the balance of antibodies may calm that down. That would make some sense to me but I find it hard to see that a random mixture of other people's antibodies has a high chance of getting things right. It's all a mystery.

So the question one has to ask is whether or not gamma globulin does really work when people say it does. It has been used for lots of conditions but there are very few proper trials. Moreover, once a really effective treatment comes along gamma globulin tends to be forgotten. The one condition where it does seem to have a consistent effect if immune thrombocytopenia, but that could be related to the complex formation issue which might be particularly relevant to destroying platelets. The mechanism that destroys platelets is probably the same one that clears up complexes. This would not apply to other conditions much.

I tried using gammaglobulin as part of a schedule with rituximab to try to stretch out the benefit and got no joy, but only tried in two patients. My instinct is that it is not going to be a major answer and it has the disadvantage that it is not clear what it would tell us about mechanism. There is also the problem that there is a shortage of gammaglobulin and this is a worry because there are people who are born without gammaglobulin and for whom replacement if essential so I think any use of gammaglobulin for other conditions needs to be properly justified.

 

[deleder2k]

Thank you. I guess gammaglobulin is not the answer we're looking for, but it is quite interesting. From my understanding it does not have any serious side effects except from anaphylactic shock and the general risk of infection from a blood product. I have seen some trials done, but they suffer from the same criteria problem like many other studies, especially old ones. It is strange that we have not seen more trials. If M.E is an autoimmune disease, it sounds logic Rituximab and gammaglobulin produced a significant effect in some cases.

As gammaglobulin is a blood product, I guess that shortage will always be a limiting factor. I heard that theres research going on to produce it chemically (?). That would eliminate the risk of infection, and could be cheaper to produce in the long term.

I went to my specialist yesterday, and if I'm not included in the Rituximab study, I think gammaglobulin is the next step. If side effects aint a problem, I don't see what I can loose.

 

[Jonathan Edwards]

It may be worth trying gammaglobulin, since side effects are uncommon, as you say.

I think there has been talk of producing bioengineered 'gammaglobulin' but I am not sure how feasible this really is. Remember that you already have a good stock of about 100gm of your own 'gammaglobulin' circulating. To be any use as a treatment you need gammaglobulin that is like other people's and not like yours - but what would that mean? If you have no gammaglobulin, because of congenital deficiency it might make more sense but then you would want a mixture of antibodies against about 500 infections so maybe the bioengineering would require making 500 monoclonal antibodies and mixing them up. That would not be cheap! For autoimmune disease the useful antibodies for each disease might be different so again you might need a very complicated mixture if you wanted a single product and it might take years to discover what the mixture should be. It's all very peculiar, but that's not to say that it may not be useful.

 

[greeneagledown]

@deleder2k -- In the open-label phase 2 Rituximab trial done at Haukeland, do you know what the dose of each of the six infusions was? Did they do six 500 mg infusions, or six 1000 mg infusions? I know in the placebo-controlled trial, they did two 500 mg infusions. Just wondering if they upped the dose of each infusion for the subsequent open-label trial, or if they merely increased the number of doses.

Thanks!

 

[deleder2k]

I am pretty sure we're talking about 500 mg infusions, but I don't know that for a fact. Maybe @Jonathan Edwards knows...?

Satellite.pdf

They say nothing about changing the dose here..

 

[Jonathan Edwards]

I am pretty sure we're talking about 500 mg infusions, but I don't know that for a fact. Maybe @Jonathan Edwards knows...?

Satellite.pdf

They say nothing about changing the dose here..

I can't remember for sure but I think the Norwegians are using 500mg per metre squared body surface area. In actual drug amount terms that is likely to be about 800mg for a slim male. It can be as little as 700mg and as much as 1000mg depending on your size. The oncologists always titrate to metre squared. In RA we rounded it up so as not to be throwing away half a bottle of drug in the pilot studies. The drug company never changed that so we have fixed dosages for the RA license. In reality it probably does not matter much. As little as 500mg per dose probably has much the same effect, maybe even less, but there may be some people who benefit from more.

 

[Snow Leopard]

Some people have asked why we need another trial on top of the Norwegian study about to start.

My view is that having the results replicated by an independent and experienced group, along with the results of the current Norway study is the minimum needed to get the drug approved for treatment in most countries. It will also go a long way towards finally stimulating some research as it will give a foothold and put out a big "please explain message" to encourage others to join the field. Well assuming these two teams haven't solved the mystery in the mean time.

 

[Sasha]

I can't remember for sure but I think the Norwegians are using 500mg per metre squared body surface area. In actual drug amount terms that is likely to be about 800mg for a slim male. It can be as little as 700mg and as much as 1000mg depending on your size. The oncologists always titrate to metre squared. In RA we rounded it up so as not to be throwing away half a bottle of drug in the pilot studies. The drug company never changed that so we have fixed dosages for the RA license. In reality it probably does not matter much. As little as 500mg per dose probably has much the same effect, maybe even less, but there may be some people who benefit from more.

I hope this isn't off-topic but I'm just curious why it's by body surface area rather than volume (or weight)?

 

[Jonathan Edwards]

I hope this isn't off-topic but I'm just curious why it's by body surface area rather than volume (or weight)?

The truth is that it isn't really surface area either, because nobody is going to measure up people's skin surface area. You would probably need to make them a wet suit and then cut it into squares and add up how many. I think what happened is that when pharmacologists were studying drug metabolism they found that the dose each person needs to get the same blood level and effect on cells goes up not with the body weight, nor just with your height, but with a measure that is closer to the square of the height than the cube (cube would be weight if we were all the same proportions).

It makes sense because for two people of the same height one who is twice the weight of the other probably has a lot more fat cells, which contribute very little to active metabolism, so does not need twice the dose, only perhaps 1.6 as much. The formula called 'body surface area' is calculated from both height and weight and seems to be about right. (One method is to use the square root of the height times the weight. If we were all the same proportions this would be proportional to the square root of the fourth power of the height - in other words to the square of the height, which would be an 'area'. This is really an imaginary area and although the formula adjusts it to more or less surface area by multiplying by a constant this is irrelevant, since you then have to multiply by another constant for each drug.

It is by no means irrelevant to ask why rituximab is dosed this way. The surface area formula was found to work for old fashioned drugs, which are small chemical molecules. It may not be sensible for rituximab for several reasons. And after all most drugs are prescribed at a fixed dose. The metre squared dosing was used chiefly for toxic anti-cancer drugs where you have to be careful not to overdose. Since high doses of rituximab do not seem to give any more side effects the real reason for getting the dose right is to minimise cost so that we can afford to treat more people.

 

[Sasha]

That's interesting - I didn't know that drug doses were calculated by initial testing. I had thought doses were calculated in relation to weight only. So the Rituximab dose formula isn't based on testing of Rituximab itself?

 

[Jonathan Edwards]

That's interesting - I didn't know that drug doses were calculated by initial testing. I had thought doses were calculated in relation to weight only. So the Rituximab dose formula isn't based on testing of Rituximab itself?

Nobody knows what the right dose of rituximab is. The original dose recommendation of 375mg/metre squared x 4 doses was based on just how much drug they had in the fridge when they did the pilot study. Over a period of twenty years various bits of evidence have suggested that the dose we use for autoimmunity is roughly right but it is not well established. The current trend for giving two doses for induction is really just based on how much drug you can reasonably give in a day. The spacing apart of two weeks is an artefact of my pilot trial with cyclophosphamide that people have stuck with because they do not know where it comes from.

BUT, the one thing I would say is that Drs Fluge and Mella are developing the longer term treatment schedule in an extremely intelligent and imaginative way. They are watching exactly what is happening as they go along and adjusting accordingly. It might be possible to get away with a much smaller initial dose but I suspect their follow up doses are pretty much right.

 

[Sasha]

Nobody knows what the right dose of rituximab is. [...] BUT, the one thing I would say is that Drs Fluge and Mella are developing the longer term treatment schedule in an extremely intelligent and imaginative way. They are watching exactly what is happening as they go along and adjusting accordingly. It might be possible to get away with a much smaller initial dose but I suspect their follow up doses are pretty much right.

This is all very interesting (and unexpected). Do you think that Drs Fluge & Mella's work (and perhaps your own upcoming work) on Rituximab dosing in ME will have implications for Rituximab in other conditions such as RA and cancer? If so, I'm wondering if that's going to help draw attention to the ME work and help get ME taken more seriously.

 

[Jonathan Edwards]

This is all very interesting (and unexpected). Do you think that Drs Fluge & Mella's work (and perhaps your own upcoming work) on Rituximab dosing in ME will have implications for Rituximab in other conditions such as RA and cancer? If so, I'm wondering if that's going to help draw attention to the ME work and help get ME taken more seriously.

An interesting thought. The schedule for treatment in RA and other autoimmune diseases tends to be what the drug company wanted it to be - as much drug being used as possible. Fluge and Mella are developing a more intelligent protocol. If that works then it could well feed back to other conditions. The real problem is that usually these drug schedules are devised by the companies. And for rituximab the company does not even want to develop it because it is off patent. It may be that F and M have broken a pattern with this in a way that could be useful in the future.

 

[deleder2k]

The probability that patients included in the new study are likely to experience a significant effect lies around 67%. I assume that Fluge and Mella have tried Rituximab on so many patients, that we could say that the number 67 won't change much. Is the effect as good as we see in other autoimmune diseases such as R.A? If i'm not mistaken, 75-85% of patients who received Rituximab had a 20% improvement in disease symptoms, in the study by @Jonathan Edwards' in 2004 (Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis)

Is it possible to say why some are non responders at this point? Could it be due to the same reason that some doesn't get better with diseases with other autoimmune diseases such as R.A?

Is it likely that other dose regimes could increase the effect with Rituximab? What about Rituximab+Methotextrate?

 

[DanME]

I am not sure, if the number of 67% won't change in the future. As far as I am aware Fluge and Mella treated 33 patients so far with clinical oversight (30 in the second trial and 3 in the pilot study). This is a small sample. The numbers could still change in the third and bigger trial with 152 patients (usually in bigger trials the numbers go a bit down).

 

[deleder2k]

They've also treated more than 33 patients. They also have had studies for severe ME sufferers. I've heard the number is above 40. I am not saying that the number will be 67%, but I guess it is pretty accurate to say that it will be 67% ± 5%.

 

[Jonathan Edwards]

The probability that patients included in the new study are likely to experience a significant effect lies around 67%. I assume that Fluge and Mella have tried Rituximab on so many patients, that we could say that the number 67 won't change much. Is the effect as good as we see in other autoimmune diseases such as R.A? If i'm not mistaken, 75-85% of patients who received Rituximab had a 20% improvement in disease symptoms, in the study by @Jonathan Edwards' in 2004 (Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis)

Is it possible to say why some are non responders at this point? Could it be due to the same reason that some doesn't get better with diseases with other autoimmune diseases such as R.A?

Is it likely that other dose regimes could increase the effect with Rituximab? What about Rituximab+Methotextrate?

I think it is hard to compare effects between diseases as the measures used are so different. The 20% improvement measure in RA is actually 'more than 20% but less than 50%' and has in the past been reckoned to be on average quite a useful and noticeable improvement. The 67% in the Norwegian trial might seem a little less consistent. However, I think the Norwegians were pleasantly surprised that it was as high as this - and I think we might all be - because I doubt anybody would put their money on all MEs being autoimmune. To my mind if more than 50% of CFS cases were due to autoimmune 'MEs' that would be quite surprising. Of course the 67% in this study was against about 15% in controls so maybe the actual benefit was to 50-55% of patients.

I do not think the figure will stay the same, but I would not worry too much. Pilot studies tend to overestimate responses because they are often done on the ideal patients to treat. Large controlled trials on the other hand tend to underestimate responses because patients are often trawled for by several centres, some of which may not be that good at selecting appropriate cases. I would expect the study coming up to show a lower response rate for that reason, and I think the Norwegians do too. On the other hand the real level of usefulness in routine practice that things settle down to after licensing tends to be better than in the large studies - I would in fact guess it would match a small controlled trial like the 67% one.

As indicated above, I think the reason some people with CFS do not respond is likely to be much more fundamental than in RA. In RA everyone has an autoimmune disease (at least in seropositive RA which is where rituximab is used). Failure to respond at all in routine practice is quite rare. The main problems seem to be that some patients have such uncontrollable antibody production that the drug on its own does not make a big impact and some patients have had so much damage in the past that nothing much will help. I would expect failure to respond in CFS to indicate most often that the person did not have an autoimmune type of ME. There might also be patients with autoimmune ME for whom getting rid of antibodies took a very long time - that looks to be a problem in conditions with speckled ANA patterns related to lupus. That might require a longer schedule of treatment or some additive agent.

Ever since patients relapsed after the first pilot study in RA we have been looking for a way of increasing the power of the anti-B cell approach. Methotrexate may add some effect but it is not a B cell depleting drug at RA doses and I doubt it is that relevant to MEs. There are other drugs that target B cells, like belimumab and atacicept and combinations of these with rituximab might make sense. What might be even better might be a sequence of rituximab followed by a 'holding agent' such as a small molecular kinase inhibitor targeting Bruton kinase maybe. Another approach is to target residual plasma cells. All of this has been debated for fifteen years now but the drug companies are not very interested in trying combinations. Some time soon somebody will discover a combination with extra benefit, but it may be by chance. Changing rituximab dose may not amke a huge difference to getting a response. however, there are other monoclonal antibodies that are probably more potent than rituximab coming through so maybe that will help.