Interferons, get out!

Today New England Journal of Medicine makes public the results of a large clinical trial with more than a thousand patients comparing results of teriflunomide against placebo in MS.

Results are not spectacular, but not bad. It decreased a 30% the annualized relapse rate and reduced the rate of disability progression slightly. The best point in favour of teriflunomide is the adverse reactions profile, comparable to that of placebo. That, together with it being oral, makes it a perfect candidate for first-line therapy and likely to be suitable for a combination trial with interferons/glatiramer acetate. Another good point in favour of teriflunomide is that it shows effectiveness in a 2-year trial, which makes results stronger.

It’s the third oral treatment showing good results in a phase III trial in MS and, probably, the second one to be approved. Fingolimod is already being used in the USA, and has been approved in Europe, but it scares a little bit and that will play against it when teriflunomide comes out. The third one, cladribine, is at serious risk of being left aside. Moreover, a fourth one, Laquinimod, will be another safe option for first-line therapy in a while although phase III data are still pending.

In a few months we’ll have, at least, two oral therapies for MS that will broaden the therapeutic options and will allow to switch patients to safe, tolerable options that, to date, were restricted to painful injected treatments or powerful (but scaring) drugs.

Hope teriflunomide approval and commercialization does not take the long, shameful process that Fingolimod is suffering. In February 2010 results were published… and here we still have to give excuses to patients…


What’s going on disimmune peripheral neuropathies

Last June NeuroImmunology attended the 2011 Biennial meeting of the Peripheral Nerve Society in the Bolger Center, Potomac (MD).

We were obviously interested in disimmune disorders but, we must recognize that, probably, breakthrough, surprising and interesting works were outside our field. Genetic and acquired neuropathies sessions showed, in our oppinion, a higher level than disimmune neuropathies ones.

However, the whole meeting was pretty interesting and some useful conclusions made us think that past work may be starting to give results. I have several comments and remarks regarding disimmune neuropathies:

For me, the first and most important conclussion is the desperate need we have in knowing a lot more of disimmune neuropathies pathogenesis:

  • Guillain-Barré syndrome studies are focused almost exclusively in antiganglioside antibodies (which, to date, are the best and more solid research line in these disorders) and don’t seem to point in any other direction, cause or mechanism. However, the ambitious GBS multicentric database projected by Dr Jacobs’ group will, for sure, help in performing other kind of studies, genetic, pathologic and immunopathogenic. We hope we can move on antiganglioside antibodies and see beyond. Dr Huizinga, from Dr Jacobs group, presented their job on dendrictic cell role in GBS pathogenesis and molecules implicated in dendritic cell priming of B cells. It seems that new, non-antiganglioside, works are arising. Regarding antiganglioside antibodies, all posters presented by Dr Willison and Yuki groups were also remarkable.
  • CIDP is, by far, the less known of all disimmune neuropathies. We still debate if auto-antibodies or T cells are the effectors. Immunopathogenic studies are scarce, weak and based in imperfect models (modified from multiple sclerosis ones, like experimental autoimmune neuritis – EAN- ). The most remarkable work in CIDP and related diseases was presentation by Gerd Meyer zu Horste, from Dr Kieseier’s lab, showing a new model of CIDP obtained knocking out ICAM-1 in NOD mice. Apart from this job, Dr Kieseier’s group is the only one that consistently publishes in CIDP basic immunology, and that was evident in the number of presentations in the meeting. In the same direction of disease models, Dr Figlia, from Angelo Quattrini group presented a beautiful conference about a model of demyelinating neuropathy caused in mice by an spontaneous mutation on dystroglycan. Although pathological features resembled those of a CIDP it pops up the question if that would fit better with an inherited cause of neuropathy, taking in account that dystroglycan is a necessary element of the extracellular matrix and has nothing to do with immune system (as far as i know). Anyway, beautiful work. Neurofascin was proposed by Dr Pollard group, as a novel antigen for GBS and CIDP. However, antigens detected by ELISA always raise the question if those antigens, detected in their denaturalized situation would be detected as well in conformational, natural situations and, thus, could be pathogenic. But, again, nice stuff to work on.
  • Nothing remarkably new was presented in multifocal motor neuropathy and paraproteinemic neuropathies pathogenesis. In anti-MAG neuropathy i liked a work, by an Argentinian group (Dr Lopez and co-workers) on the protective role of MAG for motor neurons.

The other main conclusion i reached in the meeting was that the former (knowing better the mechanisms) should lead to better, more specific therapies. We are blindly trying whatever is being tested succesfully in other diseases and still have not any alternative therapy likely to become a standard treatment in the future, IVIG and steroids aside. We’ve tried Rituximab, Alemtuzumab, Natalizumab… but except the isolated case in which Natalizumab was used, nothing specifically chosen on an immunopathogenic basis. We still are eagerly waiting for a trial with Eculizumab in GBS

However, among all the IVIg and Rituximab noise, i found an interesting poster regarding therapy. A trial in rats comparing efficacy of a recombinant IgG-Fc compound that could substitute the scarce and expensive IVIg courses. It demonstrated to be as effective as conventional IVIg in EAN Lewis rats. We hope this could be the first step to a novel therapy that could avoid the need of donors that we have now with conventional IVIg.

In conclusion, although several good presentations were worth the trip, we got home the idea that more knowledge of mechanisms and more lab work is desperately needed to move forward in disimmune neuropathies. Unless we prefer to stay stuck to decades-old theories and treatments.

All the abstracts of the meeting can be found online here

Extraordinary claims…

… require extraordinary evidence. That is the heading of a “Message from the Editor” in Annals of Neurology published online in April 2011. It comments on a paper demonstrating the absence of retroviral particles in CSF of patients with chronic fatigue syndrome while criticizes the role of publishers (and researchers)  paying (too much) attention to breakthrough discoveries while they don’t care much about those same discoveries when they fail to be replicated. It also points out the role of mainstream media and the internet in amplifying these “extraordinary claims” and highlight the need of humble statements and careful replication before attracting mainstream media focus on those claims. They, as we did, compare the case with that of the CCSVI (the other way, though) and remember us the necessary slowness of science: ” […] as journal editors we have a responsibility to do everything possible to insure that data appearing in our pages will stand the test of time.”

The only thing i don’t like in that necessary message is that it will remain within the limits of Annals of Neurology readers. That is the battle clinicians and researchers need to win. The one outside the official means. If we fail to convey this message out of our limits we will lose the battle against bad, harmful, attractive science. So the scientific community has to grow public but grow around our own environments, both our clinics and, more importantly, our communities.

Chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis: a reasonable approach.

Chronic cerebrospinal venous insufficiency is a novel hypothesis, proposed for the first time by Dr Paolo Zamboni, to try to explain the elusive cause of multiple sclerosis (MS). Briefly, this hypothesis proposes that the autoimmune attack against oligodendrocytes and the demyelination process, hallmarks of MS pathology, are caused by an excessive deposition of iron around small veins in the brain. This hypothesis is proposed after having found that venous blood flow may be altered in MS patients and, attending to Dr Zamboni’s studies, that yugular and azigos veins show an increased frequency of stenosis compared to normal controls. This hypothesis has never been accepted for a number of reasons but what matters most to me are the consequences of the disregard with which the neurological community has received this hypothesis.

Nature Journal has recently published a paper about the power of social networks to movilize patients and its potential to divert funding to studies or procedures demanded by patients. The example to illustrate the power of social networks is Zamboni’s CCSVI. In Canada, the attention paid by the mainstream media to this condition and to Dr Zamboni has turned into many patients claiming for the treatment of their vein stenoses, a procedure called, not randomly, “the liberation procedure”. But not always new healers deserve and receive attention by the media. But the context with this story is perfect…for both mainstream media and patients.

Dr Zamboni’s wife suffers MS. He is a vascular surgeon, attending to his Pubmed profile, a reputed one in the field of varicose veins surgery, but he has now focused on trying to help his wife (and others) studying MS from his vascular surgeon perspective. That means he is an outsider. Someone not familiar for the “MS stablishment”. He proposes a radically different approach in a pretty frequent and severe disease with huge pharma and national funding agencies investments, a growing number of neurologists, radiologists, biologists, immunologists, etc dedicated to it and an exponential increase in its research. And proposes a “liberation procedure” to something that nowadays has no cure… The perfect context for swindlers, mainstream media misunderstood headings, pharmaconspiracy theories, personal heroisms and the perfect environment for politicians. And that’s what we have… patients rallying for something not properly studied under the certainty that all the people involved in MS care, funding, research or market have something to hide in order to keep their positions and privileges.

Zamboni proposes an etiologic pathway that presents many unsolved questions with current evidences: it does not clarify the role of HLA genetics, the Epstein-Barr virus issues, the distance-to-the-equator gradient, the early involvement in many patients of the optic nerve, the oligoclonal bands at the beginning of the disease, the selective attack to oligodendrocytes (and not to astrocytes, neurons, microglia…) and many more. But we may assume that it’s a valid hypothesis. Then Zamboni should clarify in large epidemiologic studies what he sees in small ones, he should also answer scientifically to those who have published against his theory , he would have to integrate his findings to those that already have been accepted in MS pathogenesis theories, his findings would need to be validated in a different cohort and, after that, design one or more trials clearly showing the benefits of his procedure. That is the only approach possible. Until then, being so sorry for patients, what he does should be considered iatrogenesis.

Alternative hypotheses, those that challenge a paradigm, a stablished way of thinking and doing things in any science field usually are either believed or mocked. Believed is the appropriate word because when an hypothesis leaves the field of speculation to become a truth, an absolute, peer-reviewed, well-stablished, replicated truth is neither mocked nor believed anymore. Is just a fact. Something to include in guidelines and textbooks.

Science history is full of left aside hypothesis, dead-end streets and beautiful, logic, coherent explanations never demonstrated. And that’s why science is so often unbearably slow. The process, to be fair and, at last, useful, needs to be that slow. That’s something science journalists with big sounding headings and patients with big problems don’t understand sometimes.

Before the internet era it was quite easy to condemn to oblivion those ideas that did not fit the stablished standards. Those ideas wrongly left aside because they challenged the stablished ones were always able to arise and finally prevail. The misleading, wrong or even malicious ideas were properly forgotten. But now anyone with a favorable context (such as Zamboni’s) can spread challenging ideas, regardless of being true, untrue, good or fatal. Before, we had leaders in opinion, academic hierarchies. Now we have trends and impact factors. Now,unvalidated (but revolutionary and “liberative”) proposals are available to anyone. More, they may be, though incorrect or insufficient, published in good science journals because they increase their impact factors (remember the chronic fatigue syndrome issue in Science). Experts and academy have several problems when spreading ideas, mostly with the revolutionary ones or those that challenge the ideas of the stablished experts. They are not well organized, are not fully open and don’t communicate with their patient communities properly. That means that general public, people, patients, etc, without any filter, are scientifically abandoned in the internet to the will of those with powerful and attractive (but false) ideas or to those with personal or monetary interests but bold and shameless enough to mobilize patients’ organizations and appear on TV selling their own thing.

So, in my opinion, we need to get two conclusions from the CCSVI experience (an others, the most important the mumps-measles-rubella vaccine controversy, that lead to disease outbreaks). First, that we, doctors, need to communicate better not only in private but also in those places where people go to gather information by themselves (internet, media, etc). If not, others will and that’s not desirable for neither us nor patients. And second, the only way to get treatments approved is the (unfortunately damn slow) way of science and more science. An example: check how long took to natalizumab to get approved… So, Zamboni, keep working that hard and shut our mouths up.

Progressive multifocal leukoencephalopahy and Rituximab

In a previous post we discussed the shameful oblivion in which Rituximab has been left apart because of its patent expiry date. Just this week a new paper on Archives of Neurology deepens our disappointment. Besides the great efficacy of Rituximab, maybe comparable to that of Natalizumab (or even better as seen in their phase II trials), now we know that the most scaring side effect of multiple sclerosis new drugs, the progressive multifocal leukoencephalopathy (PML), occurs much less frequently (in a similar disease, rheumatoid arthritis) than in Natalizumab.

Despite this new paper is a case series, with several limitations, i think the neuroimmunological community should think about leaving aside a powerful drug which, moreover, will be soon free of patent. A shameful story, re-visited.

Fingolimod, two years view

The last issue of the Lancet Neurology journal, has published the extension phase study of the TRANSFORMS trial. Briefly, the TRANSFORMS trial was a randomized controlled trial comparing i.m. interferon beta 1a versus two different doses of fingolimod (0.5mg and 1.25mg). Its results were published on New England Journal of Medicine on February 2010, together with FREEDOMS, a Fingolimod versus placebo trial and CLARITY, a cladribine versus placebo trial. It showed a better perfomance than interferon in annualized relapse rate, with a concerning profile of side effects and some red flags, such as the risk of developing skin neoplasms or herpetic infections. Despite that, the overall performance in that study led to its approval by the FDA and EMEA but, while its being commercialized already in the US, it’s still on its way to the pharmacy in Europe.

In the controlled phase of the trial relapse rate with fingolimod was about a 50% lower than with interferon, and 80% o f patients remained free of relapse with fingolimod while only 63% of them were free of relapse with interferon in the first year of the study. Those were quite good results. There were also good results in MRI parameters. However there were no differences in disability outcomes, in one hand probably because the EDSS is not that a precise measure and in the other hand because overall relapse rates were pretty low. Significant side effects were present in the fingolimod arm, mostly on the high those arm, being the most concerning ones two deaths of herpes virus infections (one varicella zoster and one herpes simplex encephalitis). Another intriguing fact was the higher incidence of skin neoplasms (basal cell carcinomas and in-situ melanomas) in the fingolimod arms. Also heart conduction blocks and macular oedema were more frequent on patients taking fingolimod.

With this background, an extension phase of the trial was started, switching all patients previoulsy on interferon to one of the two doses of fingolimod. It must be said that, the extension phase of the study was not blinded anymore. This extension phase does not add very much to the initial findings but confirms the good efficacy results shown on the first year and clearly demonstrates a reduction on relapse rate in the group of patients treated with fingolimod compared to their first year on the study, when they were on interferon. The reduction on relapse rate was abut 30% compared to that on the first year when patients were on interferon.

Side effects looked pretty similar to those on the first year, also more frequent on the high dose arm, but probably with a slight decrease in the percentage of patients suffering severe adverse events, including death and skin neoplasms.

The data on this extension study, though not new and probably biased by the unblinded uncontrolled nature of the study, provide additional support for Fingolimod as a strong, more effective and, most importantly, oral alternative to current conventional treatments. However, its safety issues make us wonder if it could be better, and even more tolerable, having a monthly iv treatment far more powerful, specific and, attending to the trials (and not post-commercialization surveillance studies, still lacking in fingolimod) almost as safe, called Natalizumab.

The shameful story of Rituximab in Multiple Sclerosis

Two weeks ago a few collegues from Spain and  I attended the 3rd Preceptorship Program in MS at Steven Hauser’s department in UCSF. The scientific program and the overall quality of the course were outstanding. We had the opportunity to hear and ask those that have been ahead of MS research in the last years (Oksenberg, Goodin, Cree, Baranzini and, of course, Hauser). We heard beautiful stories of genetics, Vitamin D, EB virus, in vivo imaging and, what matters most at last, new treatments. It really was an extraordinary experience. But this is not the topic i wanted to  talk about…

One of the treatment stories was one we heard before in 2010 ISNI meeting in Sitges (SPAIN), the one about Rituximab and MS.  Apart from the commercial history of Idec, Biogen, Genentech and so on, the important thing is that it all ended up in an phase II clinical trial. A revolutionary clinical trial.

It was revolutionary because it challenged the “MS-is-(for-sure)-a-T-cell-mediated-disease” dogma showing that a B cell therapy was able to achieve unbelivable results in MS. But most importantly it was revolutionary because it got a striking 91% reduction in new enhancing lessions compared to placebo and, despite being a phase II trial, achieved a 50% reduction in relapse rates compared to placebo in less than a year. These are Natalizumab-level results, but with a quite safer profile than Natalizumab. At least, the experience with other diseases yields a progressive multifocal leukoencephalopathy (PML) rate much lower to that of Natalizumab. Just 6 reumathoid arthritis (in which Rituximab is used routinely) patients have suffered PML over more than 120000 patients treated despite RA patients having used much more frequently concomitant immunessuppresants than MS patients do usually.

The results achieved in the study deserved a NEJM paper and, for sure, a phase III trial. But that won’t happen. At least not in the short term.

It turns out that Rituximab patent expires in the US in 2015. This means that, by the time the phase III is over, the patent will be over too. So, no profit then in doing such an investment. To surpass this inconvenience Genentech invented a new drug, antiCD20 as well, but humanized (Rituximab is chimeric), called Ocrelizumab, and started the whole process again. Then, obviously, we got a phase II trial with ocrelizumab in MS. Results have not been  published yet but have been presented at 2010 ECTRIMS meeting and show,as expected, an almost equal efficacy profile to that of rituximab. But a patient died on the ocrelizumab arm from an unexpected “systemic inflammatory syndrome”. That could be chance and still hope larger studies to be assured… but it was not chance. Several rheumatoid arthritis trials with ocrelizumab have been terminated because “the overall benefit to risk profile of ocrelizumab was not favorable in RA” what it really means that 7 patients died unexpectedly in the high ocrelizumab dose arms of the trials.

So, what have we now? Rituximab, an extraordinarily effective therapy, used for quite a long time now, pretty safe but that will never be approved for MS if phase III trials are not performed (and phase III trials are not planned to be performed) because that drug has become unprofitable. On the other hand we have an equally effective therapy, tested in phase II trials, to date showing a pretty less safe profile (to the point of having been stopped in other diseases) but potentially profitable if the company overcomes the safety issues. Guess wich one will be approved in a few years.

This is terrible. We don’t have so many choices to give our patients to throw away the best ones or have to wait several more years. But it’s terrible not only for MS patients… Rituximab has been tested in small case series of myasthenia gravis, neuromyelitis optica, NMDAR encephalitisLambert Eaton myasthenic syndrome, CIDP, anti-MAG neuropathy… diseases that, if MS may not have rituximab phase III trials, they won’t for sure. And, in those case series, it has shown pretty good results that need to be confirmed in order to be approved and used routinely. If a bad commercial decision halts rituximab development or commercialization for all those diseases, MS included, it will be the most shameful story in neuroimmunology. So, if not big pharma, a consortium of neuroimmunology departments should perform that expected phase III trial and bring rituximab back to neuroimmunology therapy.

If, in the meantime, ocrelizumab, ofatumumab or any other treatment can be developed and results positive it will be welcomed, but not a single effective drug should be left behind.

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