Art and Hollie's Notes from the 2005 AAN

Sun 4/10:

Julie and I flew to Ft. Lauderdale on Jet Blue, drove to Miami. Travel was uneventful. Kept up til late by fact of being roomed in "party central."

Mon 4/11:

Got up, ate, and went to the exhibit hall to set up our booth. Found out that power and carpet cost extra. Ordered those. Had someone replace our table as some workers had obviously eaten a very messy lunch on ours.

Went out to buy some things we forgot. On our way to lunch we ran into Scientific Advisory Board (SAB) member Michael Racke from UTSW. He joined us and we had a good conversation catching up on things.

We then went to the airport to pick up Hollie and Melissa. Drove them back to the hotel to check in and then went to the convention center for the exhibit hall kick-off. Pharma Advisory Board member Judy Abdalla from Teva stopped by the booth and chatted with us for a while.

We all went out to dinner on Lincoln Road.

Tue 4/12:

Hollie and I attended the Plenary Session. We walked in half-way through a session on Equipoise (researchers are not certain which arm will receive the best treatment). The next session was by Stanley Prusiner, the discoverer of Prions talking about, you guessed it, prions. Prions are proteins that misform for some (unknown) reason and then cause other correctly formed proteins to misform in the same way - effectively replicating without DNA or RNA (other than to initially create the protein). It is thought that a number of CNS diseases are caused by prions, such as Mad Cow disease.

Scientific events have something called "Poster Sessions" which are like the grown-up form of a science fair. Researchers stand in front of posters that describe their work and you can read about it and ask them questions. We went to one of the poster sessions, but did not see anything interesting that was MS related.

Hollie and I then went to the exhibit hall and checked out about half of the vendors there. We saw an interesting organization called the National Alzheimer's Coordinating Center. They were created by an NIH mandate that requires NIH-funded researchers to collect certain data on their subjects and deposit it in a central repository. We'll be following up to see what it would take to make this happen for MS.

We then went back to do some booth duty for a while. We had quite a few people stop by including Craig Schnieder from the MS Foundation. We had hoped to share our booth with them, but it didn't quite work out. We met Charlotte Libov, the Managing Editor of a new publication for Neurologists to give to their patients called "Neurology Now" www.neurologynow.com. One of the center directors involved in the MS Centers of Florida Foundation stopped by and we agreed to see how we might work together. There were many others who stopped by to chat and sign up for our mailing list and take our literature.

In the afternoon Hollie and I split up to attend each of the two parallel MS scientific tracks. Here report will describe what she saw. I attended the MS Clinical Outcomes track.

Orhun Katraci gave a talk on familial MS. His study found that a father with MS is much more likely to transmit MS to a child than a mother with MS.

The next talk was on Pregnancy with Interferon Beta. These researchers looked at the results of preganancies that occurred during drug trials. It was a small population, but the rates of spontaneous abortion, birth defects, and healthy births were not different from the general population. This does not mean it is safe to take interferons during preganancy (we still don't know), but it isn't obviously unsafe.

The next study looked at using MRI data as being predictive of treatment response with Interferon Beta-1b (Betaseron) and found that if your MRI's are active after 6 months, you are probably not responding as well as expected.

The next talk looked at the significanced of T2 lesions in RRMS. The conclusion was that accrual of T2 lesions does correlate with progression. T2 lesions by age of subject does not seem to correlate with MRI measures, but *does* correlate with clinical outcomes (disability).

The next talk was on Transverse Myelitis (a related illness).

The final talk in this session found that progression from EDSS 0 to 3 is highly variable in individuals, but from 3 to 6 is almost always 5 years. Going on disease modifying therapy (in this study that meant a chemo agent or interferons) seems to extend the median time to EDSS 3 from 9 years to 12 years. Since this was a European study, one of the main treatments used was Azathioprine.

The big event of the day was the reporting of the Tysabri results. This was to be the big unveiling of the data from the various studies, now mired in controversy and inflammatory publicity. They moved this series of talks to the BIG hall so that everyone could attend. Before the Tysabri talks they awarded MS Researcher Jack Antel the Dystel award (involving money!) and he gave an incredibly opaque talk about his research on MS immunology.

The talks on Tysabri really didn't provide any significant new data from what had already been released other than the reduced disability rates which echoed the reduced relapse rates. What I learned is that there had been 2 other deaths during the trial in the natalizumab (Tysabri) group: a melanoma which was present before entering the trial, and an alcohol intoxication death in a person with emotional lability, but no previous history of alcoholism. I also learned that PML patient #2 has stabilized and the family has asked that his status not be discussed for privacy concerns.

After the sessions we hosted a Special Interest Group (SIG) on sample banking involving researchers who collect, store, or use MS samples. The goal is to figure out how we can all help each other and leverage each other's resources. Hollie organized and ran this effort, so I'll let her describe it in detail.

Wed 4/13:

Once again we went and staffed the booth before the sessions. Tim Coetzee from the NMSS brought the new NMSS president and the new research VP, Joyce Nelson and John Richert, around to our booth to introduce us. We agreed we need to work together and we'll be arranging a get together to talk about it when we get back from the show.

Hollie and I finished our traversal of the exhibit hall that we had started yesterday. Notable booths were the NIH booth where we saw Marion Emr (whom we had met previously) and the Public Library of Science booth (free science papers online).

I went to see the MS Imaging sessions while Hollie went to see the MS Immunology track (see her report). What I saw was:

Nancy Richert (wife of afore mentioned John Richert) gave a very well presented (this is a rarity at these conferences) talk on a study looking at atrophy in MS. Her conclusion (based on a small 19 subject population) was that atrophy correlates strongly with contrast enhancing lesion (CEL) frequency. In addition, in interferon responders where the CEL frequency is practically halted have stable brain volumes, but non-responders (with progressing CEL frequency) continue to atrophy faster than the healthy population.

Jack Simon presented some preliminary results on a new imaging technique that shows nerve fibers (bundles of nerves travelling together) and superimposes the lesion imaging on them. He intends to follow the health of the fibers that pass through lesions ("fibers at risk" or FAR) to see if this will predict degeneration.

Christopher Christodolou looked at cognitive decline and MRI over 24 weeks in 26 subjects. He found that lesion load and brain volume correlated best with cognitive testing, but other MR measures did also. This supports other research that has shown a better correlation with cognitive disability and MRI than physical disability.

Catherine Dalton looked at ventricular enlargement in MS. Notable results were that there is more ventricular enlargement in SPMS which implies that the rate of atrophy may not be constant in MS. Also she found that there was weak correlation between atrophy and lesion count which might indicate that different processes are at work in atrophy and lesion formation.

Maria Houtchens looked at thalamic atrophy in MS. She found that the third ventricular width is the best predictor of cognitive impairment. She used 80 MS subjects and 24 healthy. The thalamus atrophies 20% in MS compared to healthy people.

Susan Kim looked at the Barkhof MRI criteria (used in the McDonald criteria to diagnose MS after a single clinical event) and found that this measure was not good at diagnosing MS from other CNS disorders, especially vasculitis.

Hollie and I met up in the big hall to hear more data on Tysabri. The data on the Tysabri + Avonex vs Placebo + Avonex effectiveness was presented by Rick Rudick and the safety data by (Accelerated Cure Project scientific advisory board member) Peter Calabresi. This data had all been published previously, the only addition I noticed was the mention of 2 deaths during the trial (unrelated to Tysabri) in the Avonex only group. Also, this study had no allergic reactions unlike the Tysabri alone trial.

Andrew Goodman presented data on the Copaxone + Tysabri vs Copaxone + Placebo trial which was a smaller 100 subject, 24 week study. They found 70% reduction in relapses, 62% reduction in new T2 lesions, 74% reduction in Gd+ lesions, 40% reductions in relapses (although this result did not achieve statistical significance), no serious adverse events related to Tysabri, antibodies reduced efficacy, no disease worsening, some actually improved, persistent antibodies reduced effectiveness, and the Copaxone "flushing" response was increased in the Tysabri group.

At this point my notebook was full so Hollie's notes will be needed to cover the final bits of the day.

After that we went to dinner with one of our local area supporters, Penny Kehl to chat more about her and the organization.

Thu 4/14:

Hollie and I went to the poster session in the morning. A few interesting studies, but nothing exciting.

We managed to make some good connections at both the Serono and Berlex booths to find someone to talk to about replacing our Pharmaceutical Advisory Board members for their organizations (both of whom "defected" to Biogen Idec).

There was only one MS track today so we both went to that.

Hillel Panitch talked about the use of AVP-923 on pseudobulbar affect (PBA or emotional lability - uncontrolled laughing/crying). This drug is dextromethorphan (as in cough syrup) and quinidine (which slows the metoblisation of DM). DM slows neurological signalling (which is why it supresses coughs) and has been found effective for PBA in ALS. The study involved 150 subjects and was placebo controlled (1:1). Results were a 46% reduction in # of PBA episodes and an improved quality of life and quality of relationships. Dizziness was the primary adverse event, which is a known effect of DM.

Jesus Lovera looked at the effects of Gingko Biloba on cognitive performance in MS. They used 120mg twice a day for 12 weeks and found no important differences between the GB and placebo groups. Although, as usual for researchers, he concluded that further research was necessary and warranted.

Sebastian Schimrigk presented results from a study of Oral Fumeric Acid in RRMS and found a decrease in Gd+ lesion number and volume. EDSS was stable. It was a small study and they are going to conduct a bigger one.

Samia Khoury looked at CTLA4Ig (another infused antibody based drug known as RG2077. They did a small 16 subject study with a single infusion and found no change in Gd+ lesions.

Mark Freedman has been doing immunoablation followed by autologous stem cell transplant for a while now and was presenting the 3 year data on the 1st 6 subjects. They have had no relapses, no PASAT/9HPT change, no Gd+ lesions, and MS activity has slowed or stabilized in all of them. He quickly skipped over the slide of their 1 control who was on Navantrone that showed marked *improvement* and looked way better than the other six. This caused the audience to cry out and make him go back to it and then everyone started laughing. Hadn't seen that happen at a neuro talk before.

Doug Arnold presented the MRI data for the above study. Immunomodulatory drugs seem to have an atrophy effect in general and this procedure showed a 2 year equivalent atrophy (for untreated MS) in just 4 months! They have no idea why.

L Kasper looked at a primate-based IL-12p40 antibody (that will also block IL-23) that is a drug from Centicor called CNTO1275 and has been successful in psoriasis. 16 subjects, all stable or improved EDSS over 18 weeks, MRI appears unaffected, no serious adverse events. But they'll have to do something longer for this to have much meaning.

Edward Fox presented data on a long term study of the safety and tolerability of mitoxantrone (Novantrone) from a phase IV study. Notable points is that 507 people enrolled, only 149 are still in it. There have been 6 deaths, with 2 of them considered related to treatment and a huge number of serious adverse events. Where's the press on this drug?

The afternoon MS sessions were largely on the MS animal model studies which are not that interesting to us due to an almost complete lack of applicability to humans with MS, so we skipped them.

That evening we went to dinner with another local area supporter, Maggie Sherman, who has been watching our progress since we started.

Fri 4/15:

We got up bright and early and had an uneventful trip back to Boston where the weather was not nearly so nice.

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Hollie's notes from the 2005 AAN Meeting in Miami

Notes from the scientific sessions:

Tuesday, April 12

Plenary session: We caught part of Ira Shoulson's lecture on "Equipoise and the Value of Uncertainty for Randomized Clinical Trials," which focused on how and why you should set up a study in such a manner that you do not know in advance what the results will be. We also heard Nobel laureate Stanley Prusiner, the discoverer of prions, talk about naturally occurring prions and those that have been created in labs for experimentation and study.

Multiple Sclerosis - Basic Science: Often, "basic science" lectures focus on basic mechanisms of neurology and not so much on specific MS findings, but this panel was a pleasant exception.

The first five lectures (by Junichi Satoh, Amit Bar-Or, Tanja Kuhlmann, Orhan Aktas, and Helen Andrews) discussed possible mechanisms of MS pathology and presented supporting evidence. Panelists discussed the possible roles of Nogo and Nogo receptor in MS lesions and the blood-brain barrier; different ways in which oxidative compounds can lead to oligodendrocyte cell death; the possibility that a cholesterol component of myelin might attract microglia following myelin breakdown and that these microglia might then cause neuronal damage; and a hypothesis that loss of the nodes of Ranvier leads to a distribution of mitochondria along the neuron cell body, which increases the energy requirements of the cell, and eventually causes axonal burnout.

The last lecture was by Christiane Wegner who presented the results of a postmortem study on cortical (gray matter) MS lesions. To me it seems like we still have much to learn by examining actual MS tissue, and I was particularly encouraged to see someone investigating gray matter lesions. Wegner and her team examined tissue blocks from 22 MS subjects and 17 controls. Normal appearing cortex from MS subjects was similar to control tissue in terms of cell densities and synaptic markers, but in lesional areas these measurements were reduced (as one might suspect). Also, the cortex in MS subjects was on average 10% thinner than that of controls. In terms of lesion location, half of all lesions were found at the outer edge of the cortex (the subpial region), while the rest were either inside the cortex or overlapped the cortex and the white matter.

Multiple Sclerosis - Clinical Trials I: The first item was the presentation of the Dystel Award for MS research to Jack Antel, following which he gave an overview of some of the things he has studied over the years. Then we got down to business with three presentations from the AFFIRM trial, which was the natalizumab monotherapy trial. Although these results only cover two years, they indicate that natalizumab does seem to be capable putting a brake on RRMS over this time span - what a shame that it had to be suspended.

Paul O'Connor reviewed the two-year results which showed significant benefits of the drug compared with placebo in terms of confirmed progression, relapse rate, relapse-free status, functional status and quality of life. For instance, under the most stringent definition of progression (progression must be sustained over six months), 23% of those on placebo had progressed vs. 11% of those receiving the drug.

Ted Phillips covered the safety data, which showed that adverse events (e.g., headache, fatigue and arthralgia), infections, and malignancies were similar in both the drug and placebo groups. 9% of the drug group developed antibodies which diminished the effect of the drug, but in one-third of these people the antibodies were transient. He also quickly mentioned the two deaths in the SENTINEL trial, noting that the two MS subjects who had developed PML had received 28 and 37 infusions of Tysabri.

Finally, David Miller showed the AFFIRM MRI data which included significant reductions in Gd+, T1, T2 lesions and lesion volume after one and two years. One statistic that I found noteworthy (hopefully I wrote this down right!) was that 28% of drug-group subjects vs. 6% of placebo subjects were "disease-free" (relapse-free, no progression, no new lesions) after two years.

Wednesday, April 13

Multiple Sclerosis - Immunology I: This session dealt with the immunological effects of various MS treatments and other immunological features of MS.

The first two presentations by Vissia Viglietta and Amit Bar-Or dealt with possible effects of glatiramer acetate (Copaxone) on regulatory T cells and B cells, respectively.

Patrice Lalive presented data showing that serum containing both antibodies and complement from people with MS was toxic to neurons. The effect was most pronounced in serum from people with PPMS, also apparent in serum from RRMS subjects but not in subjects with clinically isolated syndromes (CIS).

Til Menge also demonstrated a difference between subtypes of MS in terms of anti-galactocerebroside antibodies, elevated levels of which were present in 40% of RRMS, 27% of SPMS, 6% of PPMS, and 7% of CIS subjects.

Jose Alvarez-Cermeno presented findings that subjects with CIS or laboratory-supported MS who had IgM antibodies against myelin lipids in their CSF had higher EDSS in follow-up and greater numbers of relapses than those subjects who did not.

Wrapping things up, Rana Zabad discussed a small trial (10 participants) of minocycline, an antibacterial used to treat acne and other conditions; the drug appeared to increase serum levels of s-VCAM1 and IL-12p40 and decrease MMP-9 activity.

Multiple Sclerosis - Clinical Trials II: This much-anticipated session dealt primarily with the initial results of the SENTINEL trial (which evaluated the combination of Avonex and Tysabri vs. Avonex alone). I believe this was the first public unveiling of the efficacy results; the safety issues involving PML have been widely publicized and discussed. This trial included 1,171 subjects from 124 centers in the US and Europe.

Rick Rudick went over the clinical and MRI findings from the first year of the trial. As in the AFFIRM trial, the group of subjects receiving Tysabri experienced significantly lower relapse rates, fewer lesions, and longer time to first relapse. For instance, 67% of the Tysabri/Avonex group vs. 46% of the Avonex only group were relapse free at the one-year point.

Peter Calabresi had the unenviable job of presenting the safety data from this trial. He was not able to say much about the two PML cases beyond what had already been reported, unfortunately. As for other safety data, nasopharyngitis, depression, insomnia, and influenza were the most common adverse events (> 10% in both treatment and placebo arms). Infections and malignancies were similar in both groups. 10 people in the Avonex & Tysabri group experienced hypersensitivity reactions; these reactions were serious in two subjects. Similarly to the AFFIRM trial, 12% of the subjects developed antibodies to Tysabri, which persisted in approximately half.

In addition to SENTINEL, Tysabri has also been evaluated in combination with Copaxone in a trial called GLANCE. Andrew Goodman presented the results of this 24-week study which involved 110 subjects. The combination of Tysabri and Copaxone reduced the number of new/newly enlarging T2 and Gd+ lesions over Copaxone alone; it also reduced the annualized relapse rate. Adverse events were similar to those seen in the other studies; no serious adverse events related to Tysabri were seen.

The last natalizumab paper was presented by Amit Bar-Or who demonstrated using blood samples of people receiving the drug that it downregulates the surface expression on T cells of molecules such as VLA-4, inhibiting their migration across the blood-brain barrier.

Finally, Timothy Vollmer presented data from the 22,200-subject NARCOMS database on estimated availability of subjects for clinical trials. Using typical study inclusion/exclusion criteria (e.g., "treatment naïve" for MS modulating drugs), only 5.3% of the participants in the database would qualify. Assuming only one-third of people eligible actually participate in a trial, this leaves only 1.8% of the MS population that could and would participate in a typical MS drug study. If people who previously were on an MS drug but stopped treatment were included, the eligible population increases. However, these two groups may show different response to the drug being tested since previously treated subjects tend to have higher disability, more recent relapses and worsening disease than never-treated subjects, whose disease tends to be more stable.

Thursday, April 14

Multiple Sclerosis - Clinical Trials III: This was the last session we went to since we had to help break down the exhibit hall booth later in the day. Here are the highlights:

Hillel Panitch reported that AVP-923 (combination of dextromethorphan and quinidine) had a significant effect on pseudo-bulbar effect (emotional lability) in MS, as shown by a double-blind, placebo-controlled, multi-center study.

Jesus Lovera reported on a trial of gingko biloba in cognitive impairment in MS (43 subjects, double-blind, placebo-controlled). Out of a battery of cognitive tests, only one (the Stroop test) showed a significant therapeutic effect, and this effect was seen only in the most impaired subjects.

SK Schimrigk presented promising MRI results from a trial of fumaric acid in RRMS. Over 70 weeks, subjects went from an average of 4 Gd+ lesions to 0, with EDSS and ambulatory index remaining stable. This study was single-center and uncontrolled so the results are very tentative. A multicenter, double-blinded, placebo-controlled study is underway and will be reported on this winter.

Samia Khoury presented data from a Phase I single-infusion trial of Repligen (CTLA4-Ig) showing that the drug appears to have a biologic effect and no apparent major adverse events.

Mark Freedman reviewed the status of an autologous stem cell transplantation (ASCT) study being conducted in Canada. So far 11 subjects have been transplanted and six of these have reached the three year point. These six have had no relapses, no change in PASAT or 9-hole peg test, no Gd+ lesions, and a decline in T2 burden of disease. However, only one control is available for comparison (someone who met the study criteria but got "cold feet"), so evaluating the actual effect of the treatment is difficult (especially because the data on this one control appeared to show an improvement in his/her case as well!).

Doug Arnold discussed the phenomenon of acute brain volume loss after ASCT treatment, which had been suggested to be due to the resolution of inflammation and accompanying edema. However, a similar volume loss was also seen in an ASCT subject who had no signs of CNS inflammation. Therefore, the drop-off in brain volume may be due to some other factor, perhaps related to the toxicity of the therapeutic chemicals used.

Lloyd Kasper reported on a phase I dosing study of an IL-12p40 antagonist which showed that the drug was well-tolerated after a single administration and did not impair clinical status. A phase 2 study is underway.

The last presentation was given by Edward Fox, who reviewed interim data from a long-term (5-year) observational safety study of people who had received Novantrone for worsening MS. Over five hundred people with MS have enrolled in this study, some of whom are continuing to receive Novantrone and some who have discontinued treatment. Out of this group, two subjects died from causes possibly related to treatment (four other deaths were reported but were not felt to be treatment-related). 92 subjects experienced serious adverse events, but again, most were judged not to be treatment-related. Overall, the findings seemed consistent with what was already known about the safety of Novantrone.

Poster sessions:

Each day there were sessions where scientists could present their data on posters for people to wander by and read, and maybe talk with the author if they were standing there. Here are some examples:

P03.121 - found a set of immune cells that distinguish MRI-active vs. inactive newly diagnosed subjects (this set of cells might be useful in predicting MRI activity)

P03.117 - confirmed previous reports that linked infections with an increased risk of relapse; this may be due to a shift after infection to a Th1-like cytokine secretion pattern and an increase in adhesion molecule and MMP-9 expression

P05.127 - showed that IFN-b was safe and well-tolerated in a study of children and teenagers with MS; side-effects were similar to those seen in adults and adult dosage could be used in all but one of the 51 subjects treated

P05.104 - replicated the association between pediatric MS and prior EBV exposure in 17 sites in six countries: Canada, the US, Argentina, Italy, Russia, and Finland

Other happenings:

MS Sample Banking meeting: On Tuesday night we organized a meeting with about 15 scientists to discuss issues involved in banking MS blood and tissue samples for research. Everyone was quite forthcoming and so plenty of issues were put on the table! We'll be following up with a list of projects for tackling some of the key issues and recruiting people to work on them. Many thanks to Teva Neuroscience for providing an educational grant to support this meeting.

Meetings with supporters:

On Wednesday and Thursday night we were fortunate to have dinner with two of our Florida-based supporters, Penny Kehl and Maggie Sherman, and had a wonderful time talking with each of them.

Exhibit hall: