Your impression - does MS research slow down?

A board to discuss future MS therapies in early stage (Phase I or II) trials.

Your impression - does MS research slow down?

Postby Frank » Tue Jul 07, 2009 6:54 am

I got the impression, that compared to 2006/2007 the outlook and research in the field of MS therapy became less active/exciting.

Back in 2007 vaccination with Tovaxin, NeuroVax or BHT-3009 seemd to become a significant option for MS. The immunemodulatory effects of helminth were discussed and heavy immun-ablation with ASCT, Campath, Daclizumab or HDC were within our grasp.
Stem Cells as regenerative therapy showed some success in the labs and other early stage treatments like EPO, Minocycline, Pirfenidon, Symadex seemed to offer new hope in the years to come.

Of course some of these drugs have made progress in the appovement process and some imprortant Phase-III trials are running in late stage that hopefully will bring new options for MS. But beyond that, imo. there isnt much going on. What would be the next potential current phase-II drug to enter phase-III, for the near future I cant even think of one serious candidate.
The same applys for phase-I -> phase-II, back in 2007 (at least in my recollection) I heared of various candidates entering phase-II.

In addition, as we all know, vaccination is no more much of an issue these days after NeuroVax dropped out first, followed by the disappointing results of Tovaxin and BHT-3009.

Would you agree on my view or do you think my perception is somehow distorted by whatsoever?

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby dignan » Tue Jul 07, 2009 9:07 pm

Frank,

I think it depends on how you define active/exciting. I find today's pipeline more exciting than in 2006 or 2007 because there is more in phase 3 and a number of the trials are either complete or close to completion. But I hear what you're saying about phase 1 and 2.

On your phase 1 to 2 comment, I don't really think too much about phase 1. The odds are so long that anything in phase 1 will make it through to approval that to me it's not worth investing much time in learning about them. In terms of things that are in phase 2, the first one I think of is ATX-MS1467 (Apitope/Merck Serono). Last year during a short span, Apitope got a "Fast Forward" grant from the US MS Society, then teamed up with Merck Serono on the clinical trials. Other drugs in phase 2 that seem to be relatively high profile are Firategrast and Atacicept.

Don't undersell the significance of having 3 trials (UK, Israel, US) of mesenchymal stem cells ongoing now. There are no trials yet, but the research into neural precursors / progenitors I think is going to be really important.

The other part of the equation is the overall level of research going on (not just drug candidates). I did a quick Pubmed check. From Jan 1 to July 7 2009, there were 1,224 abstracts with "multiple sclerosis" added to the database. For the same part of the year, this compares to 1,208 in 2008, 1,276 in 2007 and 1,110 in 2006. So it seems like the overall interest in MS research is pretty consistent over the last 4 years. Of course those numbers say nothing about the quality or significance of the research.

I think the big thing we've seen over the last 2 years is some high-profile failures, which you point out (tovaxin, neurovax) and don't forget lamotrigine and the most disappointing of them all (to me), rituxan for PPMS. Those failures have changed my perspective a bit. I'm not going to get too excited about any particular new treatment when it's in the early stages because the odds of failure are high. I'm just going to keep believing that overall, we're slowly chipping away at this mystery and over time we'll have more and more treatments until eventually we can stop MS in its tracks.
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Postby Frank » Wed Jul 08, 2009 6:42 am

Indeed SCT is one of the most exciting fields. Is there already an established agreement on how stem cell therapy could be patented?

ATX-MS-1467 might be promising but AFAIK it just moved into phase-II after publishing some vague results from a 6 patient phase-I/IIa trail:
Although the trial was not designed to show efficacy, there is preliminary evidence of a positive clinical response to ATX-MS-1467 in two of the six patients

So imo. regarding the number of other phase-II drugs which are in phase-II since a much longer time, its rather a bad sign if ATX-MS-1467 would be one of the most promising candidates to enter phase-III.

I think one of the most problematic things with MS research is that dispite all the knowlege gained in the previous decade, drug research (beginning with our mouse model) is still focused on the old, white matter, focal inflamation model.

Within that domain pretty much everything has been tried out: from heavy immunesupression (with the PML sideeffect) to cytokine manipulation and vaccination/immune-tolerance. Of course other regimes within that field could bring some more efficiancy and less side-effects, but the potential margin for improvements/higher idustry profits will imo. be somehow moderate.

Moving from the classic view of MS to a more complex new one would be much an effort with high financial expenses. And even if the industry began moving to a new aproach it would need to spend a considerable amount time in basic reasearch. This basic research period would leave a vacuum in advanced clinical MS trials and I suspect, that what we are currently seeing (behind the ongoing phase-III tials) might be a herald of that evolution.

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby dignan » Wed Jul 08, 2009 4:08 pm

Frank,

Your conclusion sounds very plausible. That could be happening now. I don't know. But a couple of things: if you're talking about phase 2 candidates that are getting close to moving on to phase 3, you're talking about substances discovered a long time ago.

From time of discovery to first clinical trials is probably something like 5 years on average, but certainly not less than 3 years. Then the phase 1 trial, which itself might only run for a few months, still takes around 2 years when you factor in setting the trial up, recruiting, running and analyzing results. So you're 5-7 years from discovery when you start PLANNING your phase 2 trial. By the time it is planned, recruited and had a chance to run for a while, that's another 2-4 years, so anywhere from 7-11 years from discovery and you're still in phase 2. That 7 year best-case scenario actually seems too short to me too...but anyway my point is that the promising stuff you're looking for is stuff that isn't based on the new knowledge we've acquired over the last 10 years.

Another question I have is: how does anybody not working for a research lab somewhere even know what researchers are focused on right now? It takes a long time from when they do the work in the lab until it is published and we all hear about it. There seems to me to be some evidence that neurodegeneration and grey matter involvement are being researched quite extensively today. And when it comes to actual drug development research, the researchers generally need a target to go after, so if a theory sounds promising, but they haven't characterized a promising target for a drug, then they can't develop a drug.

I think we tend to over-simplify the MS research world when we say that people just believe the autoimmune model and that doesn't work. I think the most common model for MS these days is something like: an embryo is conceived and it has the genetic makeup that makes it possible to get MS. In the womb certain factors might influence development towards MS (mothers vitamin D status? other?). In childhood, environmental factors such as vitamin D status, diet, pathogen exposure or other hygeine factors influence whether a genetically pre-disposed person develops MS. Most researchers would probably say that you need some kind of herpesvirus exposure (EBV, HHV6a etc), possibly multiple viruses, and possibly there's a retroviral element.

I think all of these things are considered part of the main-stream theory. Is there any information out their to conclusively prove that this general picture is right or wrong? I don't think there is.

I think there is a missing link in the process though. All of these elements may be involved in triggering the disease, then we have a lot of information about how the disease progresses once it manifests itself, but I don't think we don't really know for sure how the disease process starts (the good old Inflammation vs. Neurodegeneration thread).

Anyway, what all this points to for me is a much messier, more incremental research world than your characterization and so I don't think things just shift en mass. Different people and organizations focus on different things at different times. I agree that companies especially get caught up in trying to make money, so they go after a target that has already been addressed by another drug, but I guess that's a separate issue. I'm not saying that I think MS research has been conducted perfectly and that there aren't people out there just trying to make money or advance their careers, I'm sure there are.

Anyway, having said all that, you may be right Frank, and we'll know in a year or two when we look at the phase 3 trial in progress. If there are fewer than there are today, then you were right...and I'll buy you a beer...
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Postby Frank » Wed Jul 08, 2009 5:51 pm

Your right none of us is directly involved in research and it does take some time (I think your time scale sounds well founded) for new discoveries to evolve to and through clinical stage. Still I would argue that if a new way of thinking had occurred in the research domain, then someone here would have noticed some publications about it and spread the word.

If there would be research efforts, lets say for glutamate-inhibitors or antiviral/antibiotic, helminth treatment I would expect first results from cell experiments and animal models within a year or two after turning efforts in that direction. In addition I would expect a range of target-oriented diagnostic trials to seriously prove the basic principles of a new approach - i.e. virus load, neurodegeneration before inflammation etc.
In the aforementioned therapeutic fields some effective substances are already approved for other conditions, so preliminary small human trials should not take that long to follow.

My point is that there would/should be a slow but somehow steady development process that should be accompanied by corresponding publications.

Anyway, thanks Dignan, for going into discussion with me on that issue!
And lets hope I'll have to go on paying my drinks for myself... :)

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
Frank
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