“Thank you for responding so positively to yesterday’s post; it clearly needs some more explanation.”
“Why combination therapies? There are two ways MS damages and or kills nerve fibres and their processes or axons. The first is by cutting them as part of acute inflammation; the so called inflammatory scissors. The second is a delayed slow process that takes months to years to play out and is called the slow burn. We think inflammation damages nerves and axons and leaves them vulnerable to degenerate in the future. The inflammation also changes the environment in the nervous system that contributes to this slow burn. What we need to do is protect nerves from this slow burn and change the environment. To change the environment we need to switch of inflammation and ongoing autoimmune response that can attack new areas. This is why we need at the base of the pyramid an anti-inflammatory therapy. When then need to add on a drug to protect the damaged vulnerable nerves from dying in the hope that they can be repaired by natural repair mechanisms within the nervous system. The repair includes remyelination, regrowth of nerve processes and adaptation and plasticity of the brain. The latter is when ‘normal areas’ take-over, or help augment, the function of damaged areas. The brain and spinal cord has reserve or extra capacity to do this. This reserve capacity is not limitless and with time and increasing damage it runs out of capacity and progressive MS ensues. This is why we now know that progressive MS is not a process that starts late, it is there from the outset, hence the need for treating progressive disease throughout the course of the disease.”
“What about primary progressive MS (PPMS)? We now know that PPMS and SPMS are the same disease and that PPMSers simply miss out on the relapsing phase of the disease. In my opinion they are unlucky, because relapses are a way of picking up MS earlier and treating it. By the time someone with PPMS presents they have run out of reserve capacity in at least one neurological system. I also beginning to realise that progressive MS affects different neurological systems at different rates. In other words reserve capacity may be exhausted in the motor system of the lower limbs first, but there is still reserve capacity in other systems that needs protecting, for example cognition or upper limb function. This is why the lessons learnt in relapse-onset disease are very relevant to people with PPMS. This is why Novartis, Roche and Teva are doing trials in PPMS; we are involved in all three of these programmes. I have therefore updated the slide to include the PPMS trials. You also need to realise that this slide is about MS@UCLP and is only a small fraction of the global activity that is occurring in the field of progressive MS, which includes both PPMS and SPMS.”
“The DE-FLAMES Trial above is looking at a putative neuroprotective agent, with a dual mode of action, that will added onto to a 1st-line DMT in RRMS. We want to target RRMS as this is where MSers have the most to gain. Our primary outcome will be a reduction in brain atrophy; brain atrophy is an integrator of end-organ damage and correlates with disease progression, reduced quality of life and cognitive impairment.”
“The question we would like to ask you is if you had RRMS would you be willing to take and additional drug on top of an anti-inflammatory DMT to see if we can slow the progressive phase of MS? We know that 1st-line licensed DMTs are not effective at slowing down brain atrophy.”
“The results of the survey below will be used in our grant application to get DE-FLAMES funded.”
“I would like to point out that four of these neuroprotective investigator-led studies we have, or will be, embarking on come from research done as part of our PROMISE 2010 programme grant. I would therefore like to take this opportunity to thank the National MS Society of the US (NMSS) and MS Society of Great Britain and Northern Ireland for their generous and ongoing support; it is much appreciated and hopefully it will lead to a licensed treatment for progressive MS.”
I think it it good that trials are starting for progressive disease. But I think one of the most important things that is needed the most is an easy way of detecting if you have ms so that you can start treatment early. If there was a blood test for this, you could probably eliminate future cases of SPMS. This might also be useful for PPMSers who are at the earliest stages of their disease as the existing therapies may be effective at this point in time.
Unfortunately, there are no blood tests to diagnose MS. We have to see if the disease ticks the box for dissemination in time and space and it cannot be explained by another identifiable process. These criteria are archaic but seem to work in about 95% of the time. Only 1 in 20 people with MS have another disease.
What PPMS trial linked to Teva are you involved in? Is it Laquinimod?
Many thanks for all your efforts. Can you give us a guestimate of when we might see initial results from these trial, partiuclarly the investigator led trials. Also, you raised a concern before that Dr Chattaways work in this area would run into problems as there's no money to pay for the sorts of trials needed to get a licence. Do you still see this as a big issue?
All these things take time. After we put in a grant application it will take 6 months to get a positive answer and 6-12 months to set-up the study, 12-15 months to recruit, 24 months to do the study and 6 months to clean up the data and analyse it. All in all this process takes about 5 years.
Yes, we have a problem with off-patent drugs. How do we get the phase 3 registration trials done. That is why we need an alternative to Big Pharma.
I think that PPMS patients are "unlucky" because they didn't have inflammation phase is too much, as there is no treatment that prevents transition from RR to SPMS.
Re: "no treatment that prevents transition from RR to SPMS". Yes this is correct as there is no transition phase. Progressive MS is present from the outset. However, all the data collected in phase 4 studies and real life show a delayed onset of clinically evident SPMS; with the newer more effective agents having a greater effect. It is clear that suppressing inflammation has an impact. The sooner you suppress the inflammation the better.
Thanks for response. I have followup question though."However, all the data collected in phase 4 studies and real life show a delayed onset of clinically evident SPMS;"What is real life experience from your practice, what can one expect from 1st line DMT? How much they can hold clinically evident SPMS?Thanks
Re: "What is real life experience from your practice, what can one expect from 1st line DMT? How much they can hold clinically evident SPMS?"Difficult with 1st-line treatments as only a minority have NEDA. With natalizumab and alemtuzumab it is different. I have several alemtuzumab MSers who I follow t hat were treated in Cambridge >7 years ago. Despite them having highly active disease they are stable. Similarly, with natalizumab, we have over 20 MSers who have been on the drug >9 years and it is remarkable how few have entered the SPMS phase. So yes, real-life experience is compatible with the data that DMTs delays the onset of clinical SPMS. The latter is also the experience of colleagues of miner from around the world; we recently discussed this observation(s) at a meeting in Switzerland.
So what is expected for that people. i.e. alemtuzumab group. If they aren't going to relapse anymore, no more lesions, they'll just start worsening and it will be start of clinical SPMS?
I think the difficulty is knowing whether you have entered the SP phase or are only relapsing. I suppose the only way to know is to see over time whether you return to almost how you were before, or whether you continue to worsen, so it's not a decision that can be made within a few weeks. Prof G said a relapse on alemtuzumb is an indication to re treat with alemtuzumab, but like I said it's impossible I think to know whether it is a relapse or the start of the SP phase initially
Hi, can you give some indication as to how long it may take to get grant funding and when this trial may be able to start? I am very interested in taking part and at the moment I seem to meet the selection criteria but realise that as I was diagnosed just over 2 years ago, if it takes a while for the trial to start I may have been diagnosed for too long to qualify.
Unfortunately, we have had a troll, or bot, that has filled in the survey multiple times. Thankfully, Google Forms makes is easy to detect this kind of aberrant behaviour. We have therefore had to delete over 270 survey responses that came in this afternoon.
In response to the troll; we can monitor how and when a person completes a survey in real-time. If it doesn't sync with page views we know someone is repeatedly completing the questionnaire. We could also put in a request to Google for the identity of the troll; anonymity cannot be guaranteed for commentators who make abusive and slanderous comments.