Art & Hollie's ECTRIMS 2007 Notes
If you are interested in the latest research in MS, you'll want to slog through this long posting.
ECTRIMS - Prague, Czech Republic
Art Mellor and Hollie Schmidt - October 10, 2007
Hollie and Art left Boston to fly to Prague with a stop over in Paris. The flights were uneventful and our baggage was off the plane quickly. It was a red-eye, so we lost most of a day arriving the following morning with little sleep (and actual red eyes).
After collecting our bags and clearing customs without issue, we hopped in a cab and checked into our hotel. We averted a week of awkwardness by convincing the clerk that we had booked 2 separate rooms and not the one room she tried to give us at first.
We unpacked, cleaned up (well Hollie did, Art remained grungy and only brushed his teeth), checked that we had net access and headed out to find the conference center and check in. This was relatively straight-forward once we found the Metro and figured out how to read the signs.
The fast, frequent, and clean trains took us to the center where we registered and picked up Hollie's poster that she'd be presenting on Friday and headed up to the poster area to tack it up. On our way back we ran into Tim Coetzee from the NMSS and chatted a bit. We then left and took a picture of Art in his Accelerated Cure Project t-shirt. We also stopped for dinner and continued an ECTRIMS tradition of photographing Hollie eating at McDonald's in other countries.
After this much not-sleeping we headed back to the hotel to get ready for the next day and grab some shut-eye.
*** Plenary Session 1: Opening and ECTRIMS Lecture *** (Art & Hollie)
Insight into treatment of MS from clinical data basing and epidemiology (C. Confavreux)
This talk was about the use of an MS registry in Europe called EDMUS that involves 240 centers and 30 countries. Dr. Confavreux discussed a series of studies conducted using the registry's clinical database. For instance, a past study about pregnancy in MS (PRIMS) showed that relapse rate dropped during pregnancy and had a rebound of increased relapses in the first trimester after birth, but returned to baseline after that.
A study (VACCIMUS) on the effect of getting a vaccination (tetanus, flu, or HepB) on relapses found no observable increase. Another study (KIDMUS) looked at MS in children and found that 2.2% of their cases had MS onset before 16. They also found that children took 10 years longer on average to reach the same disability level as someone with onset after 16, but they started an average of 10 years sooner ("10 years longer but 10 years younger").
They've shown that factors other than relapse rate relate to disability and suggest that future treatment options should consider not focusing so heavily on relapses.
They found that 57% of people with MS over 2 years who were untreated had no change in their disability level (or fluctuated up and down with no net change). 14% of people improved and 29% progressed by >= 1 EDSS point which was "sustained" for three months ("sustained" is in quotes because half of those subsequently improved again). They did not find any effect of relapses on short-term progression.
Concerning time to reach various EDSS milestones, time to reach EDSS 4 was affected by whether the course was RRMS or PPMS, and in RRMS subjects, the time between the first and second relapse. In this cohort, it took an average of 5 years to go from EDSS 4 to EDSS 6, and 3 years to go from 6 to 7 for *both* RRMS and PPMS. And while the average age of onset was 29 for RRMS and 40 for PPMS, the age to reach EDSS 4, 6, and 7 were the same for both groups.
Dr. Confavreux closed with the observation that inflammation seems to lead to relapses and neurodegeneration leads to progression of disability, but that these two processes are not associated with each other. Suppression of relapses does not stop disability and atrophy, which left him asking "is MS autoimmune with degeneration or degeneration with inflammation?" However, he was not willing to commit to the latter view even though all the data he presented was in support of it.
*** Parallel Session 1: MS pathogenesis - New insights *** (Art & Hollie)
Collaborative efforts to understand the genetic basis of MS (D. Hafler)
This was a follow-up from the recently publicized genetics findings about IL7R and IL2RA from the large MS consortium. If you happened to be stuck in a cave and missed it, you can read our summary of the original findings here.
Since those results were published, they have been replicated by George Ebers (due to be published soon). Work is now being done to better understand the role of these MS-associated genes. For instance, IL2RA is also associated with type 1 diabetes, but different variants are associated with the two diseases. The MS variant increases soluble levels of IL2RA while the diabetes variant decreases them. Soluble IL2RA increases the proliferation of immune cells but seems to quash T cells' regulatory function.
In these genetic studies, the CD58 gene was also associated with MS. The allele associated with MS results in lower expression of CD58 which leads to lower production of FoxP3, a protein involved in immunoregulation.
Adaptive versus innate immunity: which role do they play in MS? (H. Weiner)
Dr. Weiner gave a presentation about the work being done in his lab that revolves around a variety of immuno markers for controls, RRMS, SPMS, and PPMS. For example, he and his team are interested in understanding how the peripheral immune system changes through the transition from RRMS to SPMS. During this transition, dendritic cells express more CD80 and T cells make more IFN-gamma and TNF-alpha. His hypothesis is that adaptive immunity, which is antigen specific, is involved in RRMS, while innate immunity, which is antigen non-specific, drives SPMS. A question this brings up is whether aggressive and early immunotherapy could prevent conversion to SPMS.
Dr. Weiner also described the CLIMB study which will enroll 1,000 subjects with recent onset or a clinically isolated syndrome (CIS) and follow them annually for 15-20 years. So far 730 subjects have enrolled. They have found that atrophy in benign MS subjects is lower than in early MS subjects of the same age. They are also using microarrays to detect antibodies to various antigens in serum. It turns out that RRMS subjects don't have many antibodies in common with PPMS subjects. For example, RRMS subjects have more antibodies to heat shock protein 60, a marker of inflammation or immunoregulation. The team is also evaluating the Nurses' Health Study samples to look for antibody signatures that are predictive for MS, and comparing differences between serum and CSF (so far there seem to be many).
Finally, they are analyzing antibody patterns in subjects with known lesion types using Claudia Lucchinetti's classification system. They have found reactivity differences in groups 1 and 3 compared with group 2. For instance, they detected different reactivities to cholesterol derivatives, and found that when they administered these derivatives to animals with EAE, the animals got worse.
Cortical pathology in MS: is it really a late phenomenon? (W. Bruck)
Until recently, most of the focus on lesions in MS has been on white-matter lesions. MRIs aren't good at seeing lesions in the gray-matter (cortex) so they haven't been examined as closely, and just like axonal damage, cortical lesions needed to be "rediscovered". It turns out that they are extensive in progressive MS, can occur in the absence of white matter lesions, and may be mediated by antibodies. Dr. Bruck started off referencing a study from the 70's that found cortical lesions in 93.5% of samples. A recent study saw them in 90% of samples (along with extensive remyelination -- perhaps the cortex has a higher capacity for remyelination than white matter).
Even in early MS there is damage to the cortex, resulting in measurable focal thinning, atrophy, axonal pathology, and imaging abnormalities. Marmosets who are given EAE develop cortical lesions of the same types seen in MS autopsy at the same time that white matter lesions develop. Brain biopsies of early MS subjects have shown cortical lesions in 31% of cases, and again, include all of the same lesion types found in autopsy specimens (intracortical, mixed gray-white matter, etc.). Comparing biopsies of cortical vs. white matter lesions reveals less blood-brain barrier damage, less axonal damage, and less T cell inflammation in the cortical lesions.
MS - a neuronal disease? (F. Zipp)
MS subjects have a loss of lower motor neurons in the spinal cord and a decrease in CMAP amplitudes (a test of motor nerve conduction) which is also seen in EAE. Inflammation is also seen in other CNS diseases such as stroke and Alzheimer's. Could inflammation in MS be due to injury? Dr. Zipp's lab is working to understand two mechanisms related to this question:
(1) The involvement of 7-ketocholesterol, which is upregulated in MS subjects and increased in acute plaques, and which induces migration of microglia which leads to neuronal damage.
(2) The involvement of the death ligand TRAIL, which is expressed by T cells seen around injured neurons and may cause apoptosis of neurons. EAE can be inhibited by blocking TRAIL, and TRAIL blockade also ameliorates stroke and HIV encephalopathy. A clinical trial of a drug that targets TRAIL is now being initiated (I believe it is this one.)
Demyelination, transection of axons, and neuronal death can all attract inflammation, thus indicating it is possible that the inflammation in MS may not be what starts the disease off. Dr. Zipp showed some awesome videos of T cells cruising around animal and human brain cultures and targeting damaged nervous system material.
*** Parallel Session 2: CNS inflammation and neurodegeneration in MS: can we measure neuroprotection and repair through imaging techniques? ***
Due to stupidity on Art's part (looking at the wrong day on the program), he went to the same session as Hollie (in a huge room where he didn't see her) instead of coming to his assigned section. Thus we do not have coverage for this track. However, you can read the abstracts for this and every session, including poster sessions, by visiting the ECTRIMS web site, clicking on "Scientific Programme" in the left hand menu, and then selecting the appropriate day and session.
At this point Hollie and Art went off to meet with the folks from MSBase, an Australian project that is collecting lots of clinical data from people with MS from all over the world. We're going to look into how we can integrate the data we collect into their database.
*** Parallel Session 3: Neurobiology of repair in MS*** (Art)
How do some lesions remyelinate in MS and why others do not? (C. Lubetzki)
Basically the answer is, it is an "orchestration of axons and oligodendrocytes in the proper environment," but why do some remain demyelinated? It could be because of factors impairing repair such as axonal conduction block (non-conducting axons don't get remyelinated), or expression of a protein called PSA-NCAM that stops remyelination.
It could be a problem with oligodendrocytes (oligos) - a defect in differentiation of oligo precursor cells (OPC), a depopulation in OPCs, or a defect in the recruitment of OPCs to the damaged areas.
Oligodendroglial progenitor differentiation is effective in early but deficient in chronic MS lesions (T. Kuhlman)
Remyelination is incomplete in chronic MS. Possible reasons could be: lack of OPCs, inability of OPCs to differentiate, inhibitors stopping OPCs from remyelinating, lack of axons to remyelinate, or impaired signaling to tell OPCs to remyelinate.
They looked at lesions that were control, active (from biopsy), and chronic (from autopsy). OPCs were found in early lesions, not chronic. It appears that impaired maturation of OPCs into oligos is the reason remyelination isn't occurring in MS, not lack of OPCs. If this is right it is good news because it is probably easier to fix broken signaling than implant new OPCs.
On the role of glia for axonal preservation (K.Nave)
Can demyelination cause axonal loss? This speaker did not think so and pointed out that shiverer mice, which are genetically modified to have almost no myelin, do not have axonal loss. This implies that merely losing myelin is not sufficient to cause an axon to die and means that in MS the demyelination doesn't necessarily explain the axonal degeneration.
This group has created mice that are missing a protein called CNP and other mice without cellular organelles called peroxisomes. Both of these mice grow up fine, but when they get older they start having demyelination. The peroxisome negative mice also have axonal loss and inflammation. Perhaps these mice will make better models of MS.
Promoting repair in CNS (R. Franklin)
We can replace myelin by transplanting myelinogenic cells (difficult), or by promoting inherent remyelination (probably easier). Remyelination ability declines with age and is even less in old males vs old females.
This group is studying remyelination in mice. They have found that there isn't a lack of OPCs, and they get recruited to the right places, but differentiation of OPCs into oligos (which make myelin) isn't happening. This could be because of something inhibiting them actively, or a lack of signals to tell them to do their job. They have found that remyelination happens more rapidly with the removal of myelin debris, too much prevents OPC maturation into oligos.
Extensive cortical cell loss is associated with the presence of meningeal B-cell follicles in SPMS (R. Magliozzi)
Really the title said it all. This talk was very difficult for me to understand because of dense material and the strong accent of the speaker. There was basically the conclusion (title) and a lot of detail on how they found this out.
Mitochondrial dysfunction in early stages of acute MS lesions (D. Mahid)
This session had run over time quite a bit and I needed to get to the poster we were presenting, so I skipped out.
*** Parallel Session 4: Clinical trials in MS - Developments and challenges *** (Hollie)
A reconsideration of the ethics of placebo-controlled clinical trials in MS: outcomes of an international conference (C.H. Polman)
Chris Polman reviewed new committee-generated guidelines for deciding when it's ethically acceptable to use a placebo as the control arm in an MS therapeutic study. It's OK to do this when:
- There is no established therapy for the condition (e.g., PPMS, SPMS without relapses)
- Subjects refuse the established therapy (e.g., because of injection phobia)
- Subjects have not responded to the available therapies (although there is no one definition of "not responding")
- There is a lack of resources preventing use of established therapies as a control
- The study is a short-term phase 2 proof of concept trial -- although trial designers should remember that even a short time on placebo could have long-term impacts if effective therapies are available
There are many alternatives to placebo-controlled studies depending on the question you want to answer: add-on to an established drug (but these only indicate how well the drug works in combination); dose ranging studies (everyone is on the study drug); active comparator (where the study drug is compared to an existing drug); etc. The guideline developers also recommended that more emphasis be placed on patient autonomy in decision-making (people shouldn't be railroaded into a trial) and better informed consents.
Phase IIb trial of a MBP encoding DNA plasmid (BHT-3009) for the treatment of RRMS (H. Garren)
BHT-3009 is a DNA segment that includes the MBP gene which is suspended in saline solution. When it is injected, the DNA segment is taken up by muscle cells and transcribed into MBP, resulting in the presence of MBP outside of the central nervous system. The idea is that T cells recognizing MBP outside the CNS will decide the protein is friendly and will turn off their attack on it. Dr. Garren described a phase 2B trial of this treatment that involved three arms (two doses and placebo) and lasted for 44 weeks. No significant differences in adverse events were seen among the arms, and there were also no significant differences in relapses or disability (although none were expected from this very short trial). A significant reduction in Gd+ lesions was seen in the low-dose vs. placebo group. Immunological tests showed that BHT-3009 dramatically reduced MBP antibodies in those subjects who had these antibodies in their CSF.
Statistical challenges in combination trials in MS (G. Cutter)
This talk discussed how to design a combination drug trial in MS -- how to choose the size of the study population, etc. For instance, if you think the two drugs will interact in a synergistic way, your study population can be smaller.
Preliminary CHOICE results: a phase 2, randomised, double-blind, placebo-controlled multicentre study of subcutaneous daclizumab in patients with active, relapsing forms of MS on interferon beta (X. Montalban)
The CHOICE study compared Zenapax (aka daclizumab) at two doses (1 mg/kg and 2 mg/kg) used in combination with IFN-beta versus IFN-beta alone. Daclizumab is an anti-CD25 drug that blocks expansion of autoreactive CD4+ and CD8+ T cells. It was previously shown to reduce the number of Gd+ lesions in MS subjects with an efficacy sustained over 2 years. The CHOICE study recruited 230 subjects who were already stable on IFN-beta and evaluated number of Gd+ lesions as well as relapse rate and safety.
The groups that received the combination treatment had fewer Gd+ lesions and relapses than the IFN-beta only group. Infections were similar among the arms, although the daclizumab groups had a higher incidence of serious infections. Larger studies of daclizumab are now being planned.
Proof-of-concept trials of neuroprotection in MS: design and outcome markers (D.H. Miller)
Dr. Miller gave an overview of outcome measures that might be useful in assessing neuroprotection in MS trials. A number of approaches are being evaluated, but none of them has achieved "gold standard" status yet.
- Biomarkers: A network called BioMS-eu is being set up to support biomarker evaluation using CSF and other tissues. Currently needed are cross-lab standardization and consistent correlations between biomarkers and clinical measures. For example, studies of anti-myelin antibodies have produced contradictory results as predictors of conversion from CIS to MS. Markers of axonal damage are actively being investigated and would be quite helpful in assessing neuronal health.
- Optical coherence tomography (OCT): Many recent studies using OCT have shown retinal fiber thinning in MS, even in eyes with normal vision. OCT measurements have been correlated with atrophy and disability. Questions needing to be answered include whether OCT is useful in longitudinal studies, whether retinal thinning is representative of global atrophy, and whether OCT outcomes correlate with clinical course.
- MRI measures: Some measures currently being evaluated for markers of neurodegeneration include T1 hypointense lesions (limitations are that these can be reversed, are never seen in the spinal cord, and don't give any information about normal appearing brain tissue); MRS measurements of NAA (limitations include low signal/noise ratio, low resolution, poor reproducibility); and diffusion tensor imaging. Atrophy measurements have shown robust correlations with disability and clinical course (RRMS vs. PPMS); however, their sensitivity over time is limited. No clinical trials have yet demonstrated a major effect on atrophy. However, a trial of lamotrigine in SPMS that is underway is using brain atrophy as its primary measure.
Clinical effect of the neuroprotectant MN-166 in relapsing forms of MS (R. Gammans)
MN-166 is also known as ibudilast and is used in asthma and post-stroke recovery. In this 24-month trial, 297 RRMS and SPMS subjects were divided into three arms -- placebo (these subjects would switch to drug after 12 months), 30 mg/day, and 60 mg/day. One-year data showed only a modest reduction in active lesions in the treated vs. placebo groups. However, a statistically significant slowing of brain atrophy was found in the higher-dose subjects vs. the placebo recipients. Also, the time to first relapse was longer and the percentage of subjects who were relapse-free was higher in the higher-dose group.
Side effects were generally mild and any serious adverse effects were not thought to be related to treatment. Dr. Gammans recommended continuing evaluation of the drug at even higher doses, and assessing its possible neuroprotective effects.
During the break, Hollie and Art stood by the poster we were exhibiting on the Accelerated Cure Project repository. You can see a PDF copy of it here. People came by and asked questions about it. We answered them. We saw friends from the MS research community and chatted. A good time was had by all.
*** Hot Topics ***
These sessions were panels covering "hot" topics:
Art went to see a panel by E. Frohman, G. Edan, and J. Oger that presented a series of actual MS cases where patients who were on treatment had disease activity. The presenters gave info on the case and then asked the audience questions about what they would do. It was very interactive and interesting. It really showed how little we know about what to do in a specific case. Lots of guess work based on past results with others.
Hollie tried going to a presentation called "B cells and antibodies in MS" but the door to that room was locked at starting time and people were milling around outside. She went to collect her poster, and came back to find that the event staff had opened the door and let the mobs of people in, but had inadvertently shut the door again and couldn't reopen it. She opted to avoid this potential fire trap and instead went to "Early treatment: what is early enough?" already in progress.
Dr. Clanet was making the point that long-term follow-up studies of drug trial subjects have not yet proven that current MS treatments delay disability or conversion to SPMS -- the results are too sensitive to the effects of people who dropped out of the studies. He also stated the opinion that not every person with an initial MS symptom should be started on treatment at the time of diagnosis; instead, the clinician should carefully evaluate the patient's medical data, and give the patient time to understand the diagnosis and fully participate in the decision-making process. (It was unusual to hear this advice -- mostly what we hear at MS conferences are exhortations to get people on disease-modifying drugs right away -- as you shall soon see!)
Satellite symposium sponsored by Biogen Idec and Elan: "Urgency to treat: can we modify the course of MS?"
Dr. Kieseier advocated the use of Avonex early in the disease course (see!). Dr. Jawad (a rheumatologist) gave his perspectives on the use of biologics in rheumatoid arthritis. Dr. Stefoski gave an update on Tysabri. At the end of September 2007, there were approximately 17,000 people on the drug (10,500 in the US and 5,500 in Europe). No new cases of PML have been reported. The drug is being prescribed to people with MS who have rapidly evolving, severe MS and who have failed to respond to other therapies. New data support the idea that Tysabri is particularly effective in people with very active disease.
Satellite symposium sponsored by Merck Serono: "Advances in oral MS therapies"
The purpose of this symposium was to make neurologists aware of oral cladribine which is currently being evaluated as an MS treatment, although other treatments were discussed as well. Dr. P. Rieckmann made the point that oral cladribine needs to be taken for only 2-4 weeks out of the year unlike other orals which would need to be taken daily or so. (Although for an oral drug, I bet people probably wouldn't mind daily dosing too much.)
Dr. P. Vermersch gave an overview of the non-cladribine drugs currently being evaluated -- the first three are symptomatic and the last five are disease-modifying:
- Fampridine-SR: improves mobility, muscle strength, walking speed; blocks potassium channels on axons
- Cannabis (Sativex, etc.): eases spasticity, pain
- Memantine: an NMDA receptor antagonist that has shown evidence of MRI, cognitive benefits
- Teriflunomide: reduces lesion formation; blocks lymphocyte proliferation, especially in B cells
- BG-12/oral fumarate: has shown an effect on lesions; promotes T cell apoptosis, induces a Th2 shift in T cells, and downregulates adhesion molecules; may be neuroprotective?
- Fingolimod: affects lesion formation and relapse rates; traps lymphocytes in peripheral lymph nodes, may also be neuroprotective and tighten the blood-brain barrier
- Laquinomod: reduces numbers of active lesions; changes the dendritic cell response
- Firategrast: like Tysabri, binds integrins, but its trial was interrupted due to PML concerns so not much is known yet
I noted but was not particularly surprised that low-dose naltrexone was not in this list -- it too is an oral drug currently undergoing trials but it is not of interest to drug companies since its patent has expired.
Thomas Leist then reviewed the status of cladribine and the rationale for using it in MS. Lymphocytes use an enzyme called ADA to break down certain molecules that build up internally. Cladribine is resistant to ADA so it accumulates and causes the lymphocyte to die. The effect is long-lasting -- thus the infrequent dosing schedule. Other cells such as neutrophils and platelets do not appear to be greatly affected by cladribine. In the trials completed to date, cladribine has been found to reduce the number of Gd+ lesions, T2 lesion volume, and relapse rates in recipients. Current trials include CLARITY (phase 3 trial of two doses, results expected in 2009), and ONWARD (cladribine as an add-on to REBIF).
*** Plenary Session 2: The challenges of evidence-based medicine in neurorehabilitation ***
We decided to go in a little later and skip this lecture since it was a little distant from Accelerated Cure Project's mission and we were still catching up on our beauty sleep.
*** Parallel Session 5: Haematopoetic stem cells in MS *** (Hollie)
Animal studies with haematopoetic and non-haematopoetic bone marrow-derived stem cells: their properties and the scientific basis for clinical applications in MS (D. Karussis)
Hematopoeitic and mesenchymal stem cells -- cells that reside in bone marrow -- are both capable of differentiating into CNS cells such as oligodendrocyte-like cells if cultured in the right conditions. It has also been shown that these cells can migrate into the brain. This makes autologous (self) bone marrow transplant a possible candidate for treating MS and other diseases. Dr. Karussis described initial results from a small on-going pilot study in MS and ALS where bone marrow cells are being taken from the subjects, cultured, and then reinjected into the subjects. Many patients have stabilized or even improved, and no major safety issues have been seen so far. It will be interesting to see how this ends up.
Present status of HSCT in MS (G.L. Mancardi)
Dr. Mancardi covered some of the recent findings in AHSCT (where the immune system is wiped out and then rebuilt using the patient's own stem cells). The treatment appears to completely reconstitute the immune system, creating changes in cell populations and new clone cell repertoires. A review of multiple studies found that 63% of the treated population have stabilized or improved (37% worsened) at a mean follow-up of 41 months. AHSCT appears to block the formation of new Gd+ lesions at up to 42 months post-treatment. Brain atrophy is increased for a year or two following the transplant, but then appears to level off. Autopsies of AHSCT recipients who died post-transplant have detected evidence of continuing demyelination and neurodegeneration, but it should be noted that these autopsies took place only 1-2 months after treatment.
In Europe, 300 MS subjects have been treated so far, with a mortality rate due to transplantation of 2.3%. An American trial is underway involving subjects with less-advanced MS (EDSS between 3 and 5.5) and another is being conducted in Europe comparing AHSCT with mitoxantrone. Data from a series of 60 subjects (two of whom died) showed that only 5% of RRMS subjects worsened after transplant vs. 40% of SPMS subjects, indicating that like other therapies, AHSCT is more efficacious in RRMS than SPMS. Because of its high mortality rate, Dr. Mancardi recommended that AHSCT only be used in rapidly-evolving MS that is unresponsive to conventional therapies (sounds very similar to the Tysabri recommendations).
Immune ablation and autologous stem cell transplantation for aggressive MS: interim 5-year report (Mark Freedman)
Mark Freedman presented interim data from the Canadian MS bone marrow transplant study. This study also included less-severe MS subjects (EDSS between 3 and 5.5). So far they have identified 25 candidates, 17 of whom have been transplanted. These subjects have experienced no relapses at all, as well as no new Gd+ lesions. A mix of improving/stabilizing/worsening has been seen. Lesion volumes have generally declined. Several cases have showed delayed improvement in functional areas, such as regaining of lost vision. (Perhaps this is evidence of neural repair by stem cells?) One subject's oligoclonal bands disappeared after transplant, but all the others who had them at baseline still have them.
The French-Italian Mitoxantrone-Interferon-beta Trial: a 3-year randomised study (Gilles Edan)
At this point the organizers apparently ran out of presentations on stem cell transplantation, so we switched over to more drug trial results.
Dr. Edan described a study comparing mitoxantrone for 6 months followed by IFN-beta for months 9-36 vs. just IFN-beta for 36 months. Those receiving mitoxantrone first had a delay of "confirmed" (3 month duration) progression, as well as reduced relapse rate, delayed first relapse, and increased chance of remaining relapse-free.
Secondary acute myeloid leukaemia following long-term treatment with mitoxantrone in patients with MS (I. Bosca)
A review of MS patients at a clinic who had received mitoxantrone identified four (2.83%) who subsequently developed leukemia. This worked out to 0.84 cases per 100 person-years of exposure, and development of leukemia was not associated with age, dose, or gender. In the medical literature so far, 21 cases have been described of acute leukemia developing after mitoxantrone treatment for MS. (During the Q&A period, some attendees indicated that 2.83% was a higher incidence rate than they have seen in their practices.)
Treatment of active SPMS with treosulfan (H. Wiendl)
Treosulfan, also called Ovastat, is used as a treatment for ovarian cancer and is known for a favorable side effect profile. It has been shown to inhibit lymphocyte proliferation and migration, making it a good candidate to investigate in MS. In a proof of concept study, 11 subjects with active SPMS were administered treosulfan and followed for a year. No further relapses were seen during the 12 months of the study (before the study, the subjects' relapse rate was 1.5/year on average). EDSS scores mostly stabilized or improved, as did MRI measures. Two subjects had to discontinue treatment due to lymphocytopenia. The researchers are now recruiting subjects for a phase 2 study which will last for a year and compared different doses to placebo.
*** Parallel Session 6: Imaging repair *** (Art)
Art decided to go to the right room this time, so we covered both tracks.
Perspectives of fMRI (P.M. Matthews)
This speaker talked about how remission in MS can be explained not only by remyelination, but also by functional plasticity in the brain. Using functional MRI (fMRI), where they can image your brain while you perform a task to see what parts of the brain get used, they were able to see that people with MS recruit other parts of the brain to do work to overcome damage.
To demonstrate that this is a natural behavior of the brain, they used Transcranial Magnetic Stimulation (TMS) to disrupt the "usual" area that the brain uses for a task in healthy people and saw that their brains shifted the work to the same alternate area as they saw in people with MS. Brains are cool.
Imaging demyelination and remyelination in the CNS: the promise of positron emission tomography (B. Stankoff)
If we are going to develop therapies that restore myelin, we will need a way to image myelin (so we can see if the treatments are working). MRI can't do this yet, so this researcher is looking at using PET. In order for PET to image something, it needs to have a ligand (injected chemical) bound to it that PET can pick up. This ligand has to have a lot of special properties: it must bind to myelin well, it shouldn't bind to other things, it has to get through the BBB, it has to clear from the brain in a reasonable amount of time, and it needs to be safe.
The speaker presented the results of a compound called BMB (and some others) that have most of these properties, although w/imperfect specificity. Hopefully they'll get it perfected soon.
Serial MR spectroscopy of white matter in the first 3 years after the onset of a clinically isolated syndrome suggestive of MS (K.T.M. Fernando)
They used proton MRS to look at a series of markers (NAA, Cho, Cr, Ins) related to various processes thought to be involved in MS. Looking at CIS (people with a first demyelinating event) they saw a large glial response early on and not much axonal damage.
What does fMRI offer for imaging repair? (M.A. Rocca)
This was very similar to the first fMRI talk but they postulated that some disability in MS may be caused by maladaptive recruitment of other areas (i.e. the brain tries to compensate, and does it wrong).
Evidence for enhanced functional recruitment of cervical cord in relapsing MS (F. Agosta)
Apparently very few fMRI studies have been done on the spinal cord (they generally do the brain). Lots of discussion of how they did this with the conclusion that they saw abnormal patterns of activation in the C-spine of people with MS.
We broke for lunch and decided to forgo the provided bag lunches (although later we grabbed the desserts out of them) and head to the hotel across the street for something more palatable. After solving the mystery of how to get into the building, we found our way to the "Beer & Bowling Diner" restaurant.
The menus urged "Let's Burger!" and we couldn't resist that call, so in we went. Past the bowling alleys (in the restaurant) to the host who seated us. Seeing the approximately $24 price on the burgers, we opted to "Not Burger!" and ordered something with a more sane price tag. We also did not get the unusual Coca-Cola product "Coke Blak" which we learned was Coke with coffee in it. Art (being from Wisconsin, the Bowling Capital of the World) winced at the poor technique of the school-age girls occupying the bowling lanes.
*** Parallel Session 7: Update on new treatments *** (Art)
Monoclonal antibodies (H-P. Hartung)
This talk was a rapid review of the various MS drugs in the pipeline that are monoclonal antibodies (any drug whose generic name ends in "mab" is one - e.g. Tysabri is natalizumab).
The drugs mentioned were:
- daclizumab: anti-CD25 IL-2 receptor antagonist
- alemtuzumab: anti-CD52 (yes, 52, not 25) which depletes T-cells
- rituximab: anti-CD20, depletes B-cells
- aticicept: BLyS and APRIL antagonist
New oral agents (L. Kappos)
Similar to the previous talk, this was a review of oral MS drugs in the pipeline that have completed Phase II trials. The drugs mentioned were:
- cladribine: kills lymphocytes, Phase III to complete in 2009
- teriflunomide: RA drug, Phase III to complete 2009/2010
- FTY 720: traps t-cells in lymph nodes, multiple Phase III trials to complete in 2009 and 2010
- BG12 (fumarate): Phase III just started
- laquinimod: Phase III recently started
- CCI-779: no info given on status
Other oral agents that are still in trials or had negative results:
- oral integrin antagonists: these are similar to Tysabri, but oral
- statins: trials ongoing
- minocycline: trials ongoing, could be neuroprotective
Does simvastatin antagonise the effect of interferon beta? Interim safety analysis of the ongoing SIMCOMBIN study (P.S. Sorensen)
A prior study using statins and interferons together reported data that showed subjects on the combination doing worse than those on placebo + interferons. They hypothesized that this might be because statins interfere with the way interferons work.
This speaker is in the midst of conducting a big study on the combination of statins and interferons and so decided to analyze the data they had collected so far to see if this was happening as a safety check. They analyzed their data and did not see a negative effect on relapse rate or lesion formation.
A randomised, double-blind, placebo-controlled study of fluoxetine for relapsing MS (J.P. Mostert)
Fluoxetine is more commonly known at Prozac. Prozac is known to increase cAMP (which is lower in people with MS) which decreases inflammation. The hypothesis is that this might be beneficial in MS.
A small study on 40 subjects (half placebo) for 24 weeks was conducted. They saw trends for improvement, but they were not statistically significant. When asked by an audience member why they did such a small study (since we know that MS requires bigger studies), the response was "not enough money." This is the kind of broken behavior that drives me insane. Why do a study when you know in advance that it isn't right? And why do they get to present at a big conference?
MS: more than a CD4 T cell mediated disease. Lessons from new animal models (E. Bettelli)
This talk was a rapid-fire stream of immunology mumbo-jumbo about a thousand different measurements of various cytokines in mice with EAE. At the end, an audience member asked "How is this relevant to humans with MS?" No satisfactory response was forthcoming.
Symadex: effecting neuroinflammation in the absence of immunosuppression (S. Karlik)
Symadex is a drug related to mitoxantrone in structure. These studies were done on guinea pigs with EAE. Normally I ignore the EAE studies, but this one had a surprise ending. This drug did not prevent the onset of EAE, but guinea pigs who didn't get Symadex had chronic EAE and those who did had an initial episode but recovered almost completely. Other guinea pigs who had EAE induced were given the drug later and significant recovery.
The kicker was, when they measured the immune cells in these animals, they were present in equal numbers in the dosed animals as the non-dosed animals. There was no immunosuppression, but there was remission. They hadn't figured out why yet, but very interesting.
*** Parallel Session 8: Recent failures and successes of biomarkers in MS *** (Hollie)
Biomarkers for axonal damage: quality improvement of the research area and exploitation of emerging technologies (C.E. Teunissen)
Charlotte Teunissen quickly reviewed some CSF biomarkers that are being investigated for use in MS (NAA, NfH, NfL). NfL is an early marker of axonal damage and NfH and NAA indicate axonal loss. One major problem with these biomarkers is that often in MS (and other neurological diseases), findings from one lab can't be replicated in another. The BioMS-eu collaborative project (mentioned by a previous speaker) is trying to solve this problem through standardization of protocols and validation of assays. One topic they're looking at is how long you can store samples at room temperature prior to conducting proteomics studies and still get valid data. They have found that you can store CSF at room temperature for up to 24 hours without significantly affecting some of the proteins in the sample, but whether you freeze the samples at -20C vs. -80C does affect the results. The group is also investigating protein biomarkers of RRMS vs SPMS.
The challenges of transcriptomics in MS (M. Comabella)
Dr. Comabella's team compiled a group of gene expression studies that had been performed in MS and EAE, using brain and blood samples, with or without treatment, and looked for genes that were highlighted in two or more studies. They found that studies of EAE and MS blood samples tended to highlight similar immune system genes as being over- or underexpressed. However, studies of EAE and MS brain samples did not identify the same CNS genes. They also noted many sources of variability among the studies. To generate more consistent results among studies in the future, they recommend the following:
- Validate differentially expressed genes with real-time PCR
- Replicate all results in an independent cohort
- Standardize the time of day for sample collection
- Analyze leukocyte distribution since this might affect results
- Avoid using mixed tissue in brain samples
- Exclude subjects with concurrent relapses, infections, or treatments, all of which can affect gene expression
Future directions in this field include using exon arrays to identify different isoforms (variants of proteins based on gene splicing); integration of gene expression results with genomics and proteomics data; and integration of results with MRI data.
Soluble Nogo-A, an inhibitor of axonal regeneration, as a biomarker for MS (A. Jurewicz)
Soluble Nogo-A is expressed on the growth cone of neurons, as well as in the paranode region of oligos, as well as in neural synapses. In ALS, it is expressed in muscles and it may also be abnormally expressed in schizophrenia. CSF samples from subjects with MS (114), CIS (11), NMO (3), other autoimmune CNS disorders (10), meningoencephalitis (18), and other neurological diseases (122) were analyzed for the presence of antibodies to Nogo-A. Antibodies to the 20 kilodalton Nogo-A product were found in 110/114 MS samples and 11/11 CIS samples but not in any other samples. Antibodies to a general Nogo domain (C terminal) were not found in any samples.
Antibodies to Nogo receptor as well as to MAG, MOG and MBP were found in both MS and non-MS samples. In brain tissue, the 20Kda Nogo-A protein was found in MS samples but not in control brains. (C terminal and Nogo receptor was found in both MS and controls.) So the 20kDA Nogo-A product might make a good MS biomarker. Dr. Jurewicz hypothesized that this particular protein may be released from damaged oligos and may inhibit repair. (Later I clarified with her that this marker was indeed not found in any NMO sample -- she confirmed that and said she was quite surprised to get that result.)
Gene expression profiling study in MS patients treated with interferon beta identifies a group of interferon-induced genes associated with the response to treatment (M. Comabella)
Dr. Comabella described a project to characterize peripheral blood gene expression in responders and non-responders to IFN-b (non-responders were defined as having an increase in EDSS or one or more relapses). Blood samples were taken three months after the start of treatment. Most genes that were differentially expressed were known to be influenced by type 1 interferons. The team came up with a set of genes that was 80% predictive of non-response.
Gene expression analysis suggests involvement of specific transcription factors and biochemical processes in RRMS (F. Sellebjerg)
In this study, gene expression was evaluated in 36 untreated RRMS subjects and 12 healthy controls. MRI and HLA class II genetic data was also gathered. Many of the genes that were upregulated in MS had to do with protein amino acid phosphorylation and intracellular signaling. None of the upregulated genes were specifically involved in activated CD4+ or CD8+ T cell function, or activated Th1, Th2, Tfh, alpha/beta or gamma/delta T cells. However, some genes associated with T cell memory and effector functions were upregulated in MS, as were STAT3 and STAT6. Interestingly, no significant differences in gene expression were found in subjects with active lesions vs. those without, or in those who were positive for HLA DR15 vs. those who were not.
Identification of MS related proteins in cerebrospinal fluid by advanced mass spectrometry (M. Stoop)
An analysis of proteins in CSF in MS and CIS vs. other neurological diseases (OND) identified 11 proteins that were differentially expressed in MS or CIS vs. OND. These include apolipoprotein D, complement C3 and C4A, chromogranin A, and others. The team is further assessing differentially expressed proteins and looking into their functions -- for instance, chromogranin A is expressed in neuroendocrine cells and is elevated in Parkinson's but not Alzheimer's disease.
*** Hot Topics: Homogeneity vs. heterogeneity in MS: stage-dependent or patient-dependent? ***
OK, they need to have more panels like this one. This is as close to Ultimate Fighting as neurologists get. This panel featured Claudia Lucchinetti and John Prineas - two MS pathologists who have been battling things out in the literature and editorial sections for the past 7 or so years.
A while back, Dr. Lucchinetti's lab put out a paper declaring that MS lesions come in four distinct types and that these types are unique to a patient (that is, a given patient has only lesions of one type, over the entire course of his/her disease). They suggested that this points to MS being four different diseases, or at least four different disease courses (e.g. same cause, different paths due to genetics).
Dr. Lucchinetti got up and presented the evidence in favor of this. For example, her team has found the same type of lesions in two biopsies from single patients performed some time apart (e.g., two years between biopsies). MRI features characteristic of patterns 1 and 2 vs. pattern 3 are consistent within patients over time, and subjects who have two copies of the HLA DR15 variant are more likely to have pattern 3 lesions. Her take is that there is a dominant disease pathway operating in each patient, which persists over time. She noted that this classification system applies only to active lesions which are seen in early MS -- no evidence of heterogeneity has been found in chronic "smoldering" plaques seen in later stages of the disease (SPMS).
In his response, Dr. Prineas argued that MS is one disease with similar pathogenesis in all MS patients, that the four types aren't patient-unique, and that the properties used to define the four types aren't necessarily distinct in various lesions. For example, activated complement, which is a type 2 lesion marker, has been found on all lesions in a given patient in some studies and is also seen in damaged myelin in other conditions (such as infarct). Prineas has seen some "mixed" cases, such as a type 3 lesion with remyelination (a type 2 feature) and a type 3 lesion with a perivenous orientation and deposition of complement.
Dr. Prineas picked up the question of whether pathology might change over the course of the disease. The only difference he has seen between early and late disease has to do with prephagocytic lesions, mainly seen in early MS, where the myelin is intact but there are apoptotic oligos and deposition of complement. The area is bounded by prephagocytic cells, which later attract macrophages that clear the area of myelin. Prineas stated that we need to understand the origin and nature of these prephagocytic lesions.
The question and answer period involved more comments from other top pathologists such as Bruck, Lassmann, and Barnett. Our assessment is that much of the argument revolves around the various reagents and procedures each is using and that they haven't gotten past disputing definitions. It isn't clear that all the labs are doing the same thing; maybe they should all get together sometime, analyze the same samples together, describe what they see, and resolve their discrepancies then and there. But it made for a fun (in a twisted neurological sense), if contentious, discussion.
Satellite symposium sponsored by Novartis Pharma: "S1P receptor modulation: peripheral and central mechanisms in MS" (Hollie)
This panel discussed Novartis' new MS drug, FTY720 (fingolimod). Jack Antel kicked things off by reviewing its effects on the immune system. FTY720 reduces circulating lymphocytes in a reversible fashion by 70%. The biggest reduction is in CD4+ and B cells. CD8+ cells are reduced around 50%, monocytes are unchanged, and natural killer cells are increased.
Next Howard Weiner went over findings concerning the drug's direct effect on the CNS. Because FTY720 is lipophilic, it can cross the blood-brain barrier (BBB) unlike other MS drugs. FTY720 binds to S1P receptors, which can be found on astrocytes, oligos, microglia, neurons, and neuroblasts. In vitro studies show that the drug improves oligo survival in apoptotic conditions, and promotes the maturation of oligo precursors. It also seems to regulate astrocytic signaling functions in a way that may bolster the BBB. In vivo studies in EAE show that it reverses disability, reduces demyelination, and preserves neuronal function. It has been demonstrated that these benefits are due to FTY720's direct effect on the CNS (instead of an indirect effect via the immune system) because they are seen even when FTY720 is injected right into the CNS and leaves the immune system alone. Because FTY720 seems to act directly on CNS cells, perhaps it will help people with PPMS as well.
Xavier Montalban reviewed the human clinical trial data that has released so far. A 281-subject placebo-controlled study which is now in its third year has shown significant reductions in Gd+ lesions and relapse rate in the treated subjects. Six studies are either in the active or planned stages including a PPMS study. The phase 3 studies will pay special attention to side effects seen previously including heart rate reductions and infections.
Satellite symposium sponsored by Bayer Schering and Genzyme: "Care-MS: the clinical development programme for alemtuzumab in multiple sclerosis"
Alemtuzumab is the new name for Campath, a drug that has shown promise in MS. This drug binds to CD52 and depletes T cells, B cells, monocytes, and natural killer cells.
Alastair Compston reviewed the dramatic results from previous trials (e.g., 94-97% reduction in relapse rates). He teased us by saying that results from the year 3 follow-up evaluation of the CAMMS223 trial which compared Campath to Rebif would be presented tomorrow morning. This trial was suspended early due to the death of one subject from the disease immune thrombocytopenia purpura (ITP) and the development of ITP in five other cases.
Dr. Hartung said that additional studies are now being conducted to confirm the phase 2 results. The CARE-MS I study is enrolling 525 treatment-naive subjects who are receiving either alemtuzumab (two annual cycles) or high-dose Rebif (44 ug). Outcomes will include accumulation of disability and relapse rate (which will be evaluated by blinded reviewers).
Howard Weiner covered the CARE-MS II study which is enrolling 1200 MS subjects who haven't responded to IFN-b or Copaxone. Again, the comparison arm is high-dose Rebif. A safety monitoring program is being put in place for ITP and thyroid disorders such as Graves disease that are known risks of alemtuzumab. This program includes education and monthly platelet monitoring. The study leaders believe that ITP can be averted with careful monitoring.
*** Parallel Session 9: Late Breaking News *** (Hollie)
First whole-genome scan in PPMS (F. Boneschi)
Several whole-genome MS studies have been performed in RRMS/SPMS subjects but this was the first one that concentrated on PPMS subjects. 197 cases and 234 controls were recruited, all Italian, none from Sardinia which has a different genetic make-up. It took three years to recruit this many PPMS subjects. The MS-associated variant DRB1*1501 was found to be associated with PPMS. Also associated with MS was DPP6 (dipeptidyl peptidase 6) which is expressed in the brain and spinal cord and is involved in potassium channel function. Other genes were also identified and these are being investigated further. Next steps include replicating these results, performing fine mapping of associated genes, and understanding the function of the associated genes and variants.
Pregnancy reverts the altered expression of nine discriminating transcripts in MS patients(F. Gilli)
Another tiny study -- this one analyzed the effect of pregnancy on gene transcription. Only nine MS subjects and ten controls were evaluated. The study found an MS gene expression signature in pre-pregnancy blood samples that was reversed (normalized) in pregnancy. These genes may have something to do with the reduction of relapse rates in pregnancy.
EDSS and MRI burden of disease predict cognitive status at 16 years: data from the Long Term Follow-Up Study (D. Langdon)
179 subjects participating in a multicenter trial were evaluated for cognitive performance at baseline, and then were re-evaluated 16 years later. The average EDSS at baseline was 2.5 and at follow-up was 4.5. Cognitive score at follow-up was correlated with EDSS and MRI data; it was also correlated with baseline EDSS and T2 burden of disease.
High dose intravenous interferon beta in patients with neutralising antibodies (A. Millonig)
Dr. Millonig described an investigation into whether intravenous administration of high-dose IFN-b would be able to conquer the effects of neutralizing antibodies through tolerization. So far three subjects have been treated with IV IFN-b. The treatment seems to affect MxA (an indicator of IFN-b efficacy) and neutralizing antibody levels, at least for a short time. In one patient the levels of neutralizing antibodies have remained lowered for three months; levels in the other two have returned to baseline.
Exploring recombinant human erythropoietin in chronic progressive MS (H. Ehrenreich)
Dr. Ehrenreich's neurological clinic in Germany is exploring the use of recombinant human erythropoeitin in CNS diseases like MS, stroke, schizophrenia, depression, and dementia. EPO is a hematopoeitic growth factor that has been used in anemia for 20 years. It is also a "doping" agent used by athletes to enhance their performance. There is also evidence that it functions in brain development, hence the interest in using it for CNS disorders. Dr. Ehrenreich speculated that the iron deficiency caused by EPO may also be beneficial for MS.
She presented data from an open label study in 8 MS subjects to test for safety and get initial indications of efficacy. The subjects had EDSS of 4.5 to 6.5. They were given doses of either 8,000 IU or 48,000 IU, administered weekly for 12 weeks and then biweekly for 12 weeks. They were then followed for 24 additional weeks. Results indicated a possible treatment benefit. Maximum walking increased by 200% in the high-dose group (no effect was seen in the low dose group). Improvements were also seen in EDSS and some motor and cognitive tests. No adverse events or blood pressure changes were detected. The speaker felt these results warranted a larger trial of EPO in MS.
The REGARD trial: a randomised assessor-blinded trial comparing interferon beta-1a and glatiramer acetate in RRMS (D. Mikol)
Dr. Mikol reported results from this Serono-sponsored trial, which compared outcomes in RRMS subjects receiving Rebif (high-dose = 44 ug) vs. Copaxone. This 96-week trial recruited 764 RRMS subjects with EDSS less than or equal to 5.5. No significant difference was found between the two arms on time to first relapse (the primary outcome of the study) or annualized relapse rate. The study team had to go to a subgroup analysis in order to find significant differences in relapse measures: they found that subjects with lower EDSS scores did better on Rebif on time to first relapse. No overall significant difference in new/enlarging T2 active lesions was found although, again, less severe subjects (as well as non-Russians) did better on Rebif. The Rebif group did do better in terms of number of Gd+ lesions.
Dr. Mikol attributed the lack of a significant result in the primary outcome to a lower number of on-study relapses than expected. He felt that if the study had been larger, or if the subjects had been similar in terms of relapses to those in earlier trials, they would have seen a difference. Of course, as another attendee pointed out during Q&A, it may be that they wouldn't have seen a difference because perhaps the two drugs just have similar performance.
*** Parallel Session 10: Free communications *** (Art)
A single blind, randomised MRI study comparing high-dose oral and intravenous methylprednisolone in treating MS relapses (V. Martinelli)
IV steroids are often given to MS patients for acute treatment of relapses. While often effective, they are expensive and inconvenient - often requiring the patient to go to the hospital and to have a tap left in their arm for up to 5 days. Oral treatments are cheaper and more convenient, but no studies comparing their effectiveness in treating relapses (at equivalent doses) has been done.
This study found 1000mg IV vs 500mg twice daily oral steroids had equivalent effectiveness in treating relapses as measured by reduction in enhancing lesions.
Meta-analysis of Phase II and III Fampridine trials in MS: efficacy assessment and validation of clinical meaningfulness of outcome measure (A.D. Goodman)
Fampridine, also known as 4AP (4-aminopyridine), has had a couple of trials (and one Phase III is still under way) looking at the effects of the drug on ambulatory function (ease of walking) and leg strength (or "lower extremities" as researchers call them). They looked at doses of 10, 15, and 20mg and found no difference in effect, so continued trials at the lowest dose.
Looking at the data so far, they found that 36% of people on active drug saw an improvement in walking speed vs 8% of people on placebo. They also found that this improvement was reflected in the patients' own perceptions of how well they were doing. So, if you are a responder, it appears that this drug will have benefits worth getting.
*** Plenary Session 3: Charcot Award Lecture (Art & Hollie) ***
A peculiar lesion in the cord with atrophy - is MS an inflammatory or neurodegenerative disease? (D.A.S. Compston)
This final lecture was given by Dr. Alastair Compston who received the Charcot Award in recognition of his work in MS.
Dr. Compston described a theory of MS that involves the ongoing interplay of inflammation, demyelination, and axonal injury, claiming axonal loss is a result of the demyelination, and the whole process is set off by inflammation. Perhaps if inflammation is stopped early enough in the disease, the progression could be prevented or slowed. He suggested that use of animal models or otherwise was not the way to go, but to look at the effect of treatments on human subjects with more active MS when treated early.
He reviewed the history of Campath (alemtuzumab) which was initially tried in the 1990's in a small cohort of patients with SPMS. It dramatically reduced inflammation in these patients, and seemed to have clinical benefits in at least one, but their disability progressed as did atrophy of the CNS. It seemed to be a failure in MS, but as later studies have shown, perhaps it is better suited for RRMS patients.
Dr. Compston then picked up where he left off last night with the year 3 results of the alemtuzumab RRMS trial mentioned above (CAMMS223). When the trial was suspended due to the ITP cases and death, only 20% of the subjects had had their third treatment. Therefore, at the three-year point, 80% of the subjects had had no therapy for up to two years. Even so, the data revealed a continued dramatic reduction of 73% in relapse rate at year three for alemtuzumab compared with Rebif recipients. On average, across all three years, alemtuzumab subjects had 0.1 relapses per year vs. 0.4 for the Rebif subjects. Time to sustained accumulation of disability was 71% longer in the alemtuzumab vs. Rebif subjects. In fact, EDSS scores improved by 0.39 on average in the alemtuzumab group compared with a worsening (-0.39) in the Rebif group.
In vitro testing has shown that when lymphocytes reconstitute after alemtuzumab treatment, they produce more growth factors such as BDNF and CNTF that enhance neuronal survival and growth, as well as oligo survival and maturation and myelin production. Perhaps this mechanism helps account for the disability results.
Another analysis examined whether subjects who had three doses did better over time than those receiving only two. The relapse rate was indeed lower in the three-dose group, and almost all of the subjects who had a relapse or sustained disability were in the two-dose group. This indicates that while two doses are beneficial, continuing the dosing regimen for at least another year enhances the benefits. Interestingly, of 47 subjects who were treated with Campath from 1999-2005 and who had similar clinical characteristics to this study's subjects, none have acquired sustained disability from relapses or have entered a secondary progressive phase. However, those who were initially treated with an EDSS of 6.0 or greater have progressed.
Dr. Compston concluded that these results imply that the suppression of inflammation is the key to preventing disability. Perhaps the neuroprotective component also plays a major role in the alemtuzumab results given other studies that indicate that immunosuppression may not be entirely effective. In any event, it looks like a pretty promising drug, and as mentioned before, larger trials are starting.
The nice thing about ECTRIMS ending at noon on Sunday is that there was no chance of catching a plane back to the US that late and so we had the rest of the day free. Hollie had a blast exploring Prague on foot and in the evening we both had beers at the old brewery U Flecku which was mere feet from our hotel, thus we didn't have far to stagger back. Prague is a great walking city, with beautiful architecture and a lively atmosphere (at least when the weather is nice). Best of all the prices there are quite reasonable especially when compared to the rest of Europe so you can eat, drink, and buy souvenirs without feeling too guilty about it.
We enjoyed our last breakfast buffet in the hotel (still puzzling over why anyone would eat salad for breakfast) and made it to the airport in time to catch our flight to Paris and then the one back to Boston. The USDA beagle at Logan's baggage claim sniffed Hollie's tote bag long enough to raise suspicion of illicit food items, but she was eventually allowed to walk free. One cab ride later and we were at our respective homes, hooray.