Archive for July, 2015

More is Better: Rituximab Trial Boosts Hopes for Chronic Fatigue Syndrome

The Rituximab  Story

“I was completely revitalized. Suddenly, I could be sociable again. I would go to work, go home, eat dinner and feel restless.” An ME/CFS patient in the study

The Rituximab story started in 2004 when Fluge and Mella two Norwegian oncologists noticed that some of their cancer patients with chronic fatigue syndrome were doing very well on a drug called Rituximab. In fact, they were doing too well. Not only had their cancer gone into remission but so had their chronic fatigue syndrome symptoms.

tweaking treatment protocol RItuximab

In this study Fluge and Mella tweaked their original treatment plan to produce more powerful and lasting results

Fast forward 11 years, one case series and another study later and we find Fluge and Mella not just treating ME/CFS patients with Rituximab but aggressively tweaking their formula to achieve a lasting remission in the responders and to provoke a remission in treatment resistant patients.

In the initial Rituximab trial published in 2011 Fluge and Mella gave 30 chronic fatigue syndrome patients two Rituximab infusions  two weeks apart and then followed them for 12 months. Three months into the trial there was no evidence the drug was working but 6-12 months later two-thirds of the participants had responded and some had responded in truly dramatic fashion. Years of disability and pain dropped away as some patients almost miraculously achieved normal lives.

Many of the responders, however relapsed later. In this study Fluge and Mella tried to do something about that. They gave Rituximab to 29 ME/CFS patients more often and for longer and they followed them for longer.

Rituximab

Rituximab induces B-cells to kill themselves by attaching to the CD20 receptor on them. It also enhances the ability of natural killer cells to kill them.

Originally developed and FDA approved to treat cancer (lymphoma) Rituximab is also FDA approved to treat rheumatoid arthritis and is used off-label to treat multiple sclerosis, lupus, chronic inflammatory demyelinating polyneuropathy, autoimmune anemia, Sjogren’s Syndrome and many others.  Chronic fatigue syndrome may be the first disease outside of known autoimmune disorders, that Rituximab has been tested in.

The Study

B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, Kristoffersen EK, Sørland K, Bruland O, Dahl O, Mella O. PLoS One. 2015 Jul 1;10(7):

After the two infusions in the first two weeks (500 mg/m2 (maximum 1000 mg) Rituxmab was given four more times at 3, 6, 10 and 15 months (500 mg/m2 (maximum 1000 mg) and the patients were followed for no less than three years. The participants assessed their symptom levels every two weeks and health related quality of life using the SF-36 form.

Lymphocyte subpopulations, including CD19 positive B-cells were assessed before the infusions and at 3, 6, 10, 15, 20, 24, 30 and 36 months.

In an attempt to boost their response seven of the patients who showed slow and gradual improvement after twelve months received up to six additional infusions at two month intervals.

The Participants

This was Norway but the study population looked like that found anywhere else. Sixty-nine percent of the participants were women and 31% were men. The average age was forty and the average duration of illness was nine years. The severity of their illness ranged from mild (n=5), mild/moderate (n=4); moderate (mainly housebound) (n-13), moderate/severe (n=4), severe (bedridden) (n=3). Almost 60% associated an infection with their illness, 34% did not and 7% were not sure.

Seven patients had had Rituximab before but relapsed later and three had tried it and received no or a minimal response. Nine participants had been in the placebo arm of the former study.  All met both the Fukuda and Canadian Concensus Criteria for ME/CFS.

The Results

The Responders

As in the first trial over 60% of the participants reported significant clinical improvement; i.e. they achieved an improvement in their Fatigue score ≥ 4.5 for at least six consecutive weeks. Fourteen or 78% of those  who did were described as “major responders” and four (22%) were described as moderate responders.

more is better Rituximab

More was indeed better as many of the responders maintained their response a year and a half after receiving their last treatment

Some evidence suggested that the major responders were close to functioning normally or in some cases were fully recovered.  With their average SF-36 scores showing remarkable increases it appeared that many of the responders really responded. (More is better with the SF-36).

The average social functioning score – which denotes how much a person is inhibited from functioning socially – increased from 18.4 to 70.8, the average vitality score tripled from  17.7 to 61.3, the average physical functioning score – probably a really difficult one to improve on in ME/CFS – almost doubled (42.9 – 83.3), and bodily pain scores more than doubled (32.2 to 72.3).

At the end of the trial the responders average SF-36 score meet population norms; i.e. you wouldn’t be able, using this test, to tell them from healthy people. It didn’t mean they were all healthy- the test is not precise enough for that – but they were much, much improved.

Some limited Sensiware armband data validated the findings: the number of steps the responders took at the end of the trial indicated they were about as active as normal people.

The Non-Responders

The ten people who did not respond – really didn’t respond; no significant increases in any of the SF-36 scores were seen. It appears that most of the responders do pretty well while nothing much happens for the non-responders.

Maintaining Health – the Maintenance Strategy Mostly Works

The maintenance strategy of providing Rituximab more often to produce a longer-last effect was mostly successful.  Again, those who responded to it responded well. Those did not respond – really did not respond.

The duration of the response zoomed in the responders from 25 weeks (half a year) in the first study to almost 100 weeks (two years) when taking maintenance infusions in the second study.  The responders stayed healthier longer once they were off the drug as well. Three years after beginning the treatment and a year and a half after their last infusion  the treatment was sticking for about 60% of the responders. Some former patients were clearly well.

“Eleven of the 18 responders were still in remission three years after beginning the treatment, and some have now had no symptoms for five years,” Fluge.

B-cell tests indicating the B-cell numbers of all the responders were back to normal suggested their systems may have been reset. If they’d had an autoimmune problem it had disappeared during their long period of immune suppression.

The maintenance dose did not enhance the duration of the response in everyone, however; about forty percent had relapsed a year after receiving their last dose.

The More Is Not Better (Except When it Is) …..Group

Giving Rituximab more often (at the end of one year) to patients who’d had a moderate initial response to it failed to turn them into major responders.  One person, however, who didn’t respond to the two-dose first trial, did respond to five dose second trail.

More doses of Rituximab early on, then, might help but if a year of increased dosage is not helping then it’s time to try something else. Why some people respond and others don’t isn’t clear. Sophisticated immune analyses, however, are underway to attempt to figure that out.

Concerns

Placebo Response

There’s concern about the lack of a placebo group. No treatment will ever get approval without having a placebo controlled study but I wonder how serious the placebo concern is. The long time to the response seen (several months) and the long duration of the response argue (a year and a half in some) argues against a placebo response making a difference for many.

Study Size

A bigger concern is probably the small study size.  Thus far we have  response data on a small slice of the ME/CFS population in an ethnically homogeneous region.  (The upside to doing the study in Norway is that they can apparently get things done pretty quickly; the downside is that the country simply doesn’t have the ethnic diversity the U.S. has.)

subset

The biggest questions facing the two studies done so far is how closely the study participants resemble the ME/CFS population as a whole.

We can say that Rituximab works well  and sometimes very, very well in a subset of patients but we don’t know how big that subset is. I expect the response rates to drop as more types of ME/CFS patients sample the drug. Even a thirty or twenty percent response rate would be very exciting.

The results from the multicenter trial will not be available until 2017 or 18 – two or three years. If the 152 person trial goes well it’s hard to imagine – at least from this layman – that large trials will not quickly open up in the U.S. The infrastructure and the network of physicians needed to engage in a major trial is present. They will simply need access to the drug.  With all the federal reports citing the need for better treatments a way has to be found to get the” big lug” to mount a major trial.

The Severely Ill Study

Thus far in a separate study none of the four severely ill ME/CFS patients in a small open-label study have responded to Rituximab. Four more patients are being assessed. They do not encourage the use of this very strong drug in the severely ill at this time.

The Autoimmune Question – If it Looks Like A Duck…

Chronic fatigue syndrome with it’s female predominance, it’s often infectious trigger, it’s symptoms and the changes that sometimes occur in pregnancy has always looked like it might be, at least in part, an autoimmune disorder.

Fluge and Mella’s autoimmune hypothesis ties several aspects of ME/CFS together in a neat package. First an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explain the brain fog. Several studies back up the muscle and brain issues – the question is whether antibodies are the result.

duck autoimmunity ME/CFS

If it looks like a duck and walks like a duck… is it a duck?

Thus far the Rituximab findings suggest autoantibodies play a role at least in a subset of patients. As before the responders took their sweet time – several months – to respond to the drug.  That several month time lag, though, is about how long it would take Rituximab to clear auto-antibodies from the body. That time-lag strongly suggests an autoimmune process is going on.

Increased rates of autoimmunity (41%) in the first-degree relatives of the patients buttressed the autoimmune hypothesis; a genetic predisposition is often present in autoimmune disorders.

If auto-antibodies are the key Fluge and Mella and others, however, have not found them yet.  They do have a hypothesis, though that ties several aspects of ME/CFS together in a neat package. They believe an infection triggers the body to produce antibodies that target the blood vessels and stop them from delivering normal amounts of blood to the tissues. The drop in oxygen to the mitochondria resulting from the reduced blood flows explains the fatigue, lowered aerobic capacity and exercise problems. Given the brain’s enormous need for oxygen it also explains the brain fog. it’s a theory with a nice foundation: several studies back up

We should see a paper explaining Fluge/Mella’s hypothesis soon and studies embedded in the 150 person trial will help assess whether their hypothesis is correct.

Norway!

It’s worth noting again what a remarkable role the small country of Norway has played in this unlikely scenario.  Size doesn’t always matter – and one suspects that it may be a hindrance in some cases. Two Norwegian physicians birthed the Rituximab findings, Norwegian advocates raised money and pressured the Norwegian government to do what nobody else has been able to do – fund and produce a very expensive and large treatment trial.  Not only did they do that but they did much more quickly than anyone else.

It’s a scary thing to have to depend on a small country with almost no history of ME/CFS research or on private donors in another country to follow up on the most exciting treatment finding in ME/CFS’s history.  If Rituximab works out – and it’s hard to imagine that it will not at least in part work out – the worldwide ME/CFS community will owe the two doctors, the Norwegian advocates and the Norwegian government a huge debt.

The UK is on board. It may be that UK advocates – driven by their awful circumstances – try harder when it comes to jumping on a hot treatment finding. Since June, 2013 Invest in ME has raised over $600,000 US dollars for its own Rituximab trial. According to Dr. Jonathan Edwards, who pioneered Rituximab’s use in autoimmune disorders, Invest in ME has enough money now for a small trial involving 30-40 patients.

That’s great and Norway  has already produced a much larger study and is years ahead of everyone.  That quick start is important given how long these treatment trials take and how long it can take to get approval for a drug.

A Rituximab Timeline

Let’s look at a Rituximab timeline. Fluge and Mella identified their first Rituximab responsive ME/CFS patient in 2004. Their three person case study was published in 2009.  Their 30 person placebo-controlled study was published in Oct. 2011. They began the 152 person multicenter trial at the end, if I remember correctly, of 2014. That study should end in late 2016/early 2017. It will take some time to analyze the results and then get them published. Perhaps we’ll see a paper in early 2018.

You can argue that moving from a small case-study in 2009 to a large multi-center trial beginning in 2014 is good progress and it probably is, but it’s still five years in the life of an ME/CFS patient.

The Big Lug

Much of the innovative research, both inside and outside the public sphere, is occurring in the U.S. but the Rituximab trials might never have happened for all the work that’s been done here. That’s something that ought to give one pause.  A possible new treatment for a disorder with no FDA-approved drugs occurs and the biggest and richest country in the world does nothing.

head in sand

The country with the biggest medical system in the world hasn’t figured in the Rituximab story at all yet

How does that happen? Norway got funding from both advocates and the government. UK advocates have raised $600,000 by themselves. No group has mounted a serious effort in the U.S. and federal funding for clinical trials is difficult to achieve.

It’s pretty clear right now that nothing’s going to happen around Rituximab in the U.S. until the Norwegian trial ends up in mid 2017. Say the Norwegian results published in 2018 are impressive and the U.S. gets a major year-long trial started in early 2019.  The results are in by mid-2020, they’re submitted for publication in early 2021, are published in mid-2021. The FDA examines the data from the US, Norwegian and UK trials and in early 2022 seven years from now, approves Rituximab for use in a subset of ME/CFS patients.

When U.S. – because of bureaucratic or institutional barriers or whatever, is simply sitting on the its hands everything takes longer. In another disorder the Oct 2011 Fluge/Mella study might have sparked an extensive U.S. treatment trial in 2012.  The first results of that multi-year trial might have been published in say 2015.  In this scenario with the big Norwegian study underway we’d have enough data to apply for FDA approval in two years.

An Unlikely Ally

The two studies have created an unlikely ally. Simon Wessely – the foremost proponent of the idea that ME/CFS is caused by poor coping and deconditioning – has been impressed enough by the results to call for a large trial. “There is now a strong case” he said  “to be made for a larger trial”.  Whatever you think of Wessely that’s a very helpful statement coming from a man of his background.

The silver in the lining of the United Kingdom’s embrace of CBT/GET is the extent to which they’ve funded it. The UK, per capita, has been far more generous with ME/CFS funding than the U.S. and they’ve shown the willingness to put significant dollars (or pounds) behind a treatment trial. Drug trials in the U.S., on the other hand, appear to be almost solely funded by pharmaceutical companies. Wessely – recently knighted – has a lot of pull in the U.K.  Could Wessely prod the UK government to get behind an enlarged Invest in ME Rituximab study? That would a be flip of major proportions.

Wessely also said “The belief that [CFS] is all in the mind has been around since the beginning,” he says. “It’s tragic that it might take a study like this to take sufferers seriously.” That’s quite a statement given his history. Check out how that statement jives with Wessely’s past ones in Simon Wessely’s Big Shift? CBT Icon Calls For Big Rituximab Trial

Conclusions

It was a remarkable thing to see almost half the study population exhibiting normal or near normal SF-36 and activity scores after three years.  Even if this is a small study the almost identical response rates (a strong 60 plus percent) found in it and the first study  are encouraging.

This study also demonstrated that give doses more often eliminates many of the relapses that dogged the patients in the first study and it presented more evidence that this powerful drug  is generally safe for use in ME/CFS patients.

As promising as the results of the first two studies are it should be noted that they are small studies and surprises may show up in the larger study underway. It is using the same improved treatment protocol used in this study. It’s results will probably not be published for several years.

In the meantime, this study prompted a major CBT advocate to call for larger studies and a smaller UK trial is in the process of being produced. (You can support that study here.)