Wow who would have thought you would get improved function in advanced SPMS? #ThinkHand #ECTRIMS2016 #ResearchSpeak #MSBlog
“The poster below is one of my ECTRIMS highlights. It has made me think differently about MS, in particular about the mechanisms behind the improvement in neurological function. In short if the natalizumab in SPMS trial (ASCEND study) had been designed with the primary outcome being sustained improvement in function then we would have had a drug available for SPMS. It is quite amazing given what ‘we think we know about SPMS’ that this study was positive. I thought that advanced SPMS was progressive with little room for recovery of neurological function. How wrong I was!”
“As you know the ASCEND trial was ‘negative’ in that it did not hit its primary outcome at 2-years, which was a composite loaded with lower limb function (EDSS and timed-25ft-walk or T25W). However, the trial was positive on the 9-HPT. In other words SPMSers on natalizumab have something to gain from natalizumab in relation to protecting arm and hand function. In fact natalizumab was so good in the ASCEND trial that it almost flat-lined upper limb function. Why the difference in outcomes between lower and upper limbs? I have made the argument many time before that if you have lost your reserve capacity in a particular system, which was the case in the lower limbs in this study (most subjects had an EDSS of >= 6.0) then it would take years to see a positive outcome. I have referred to the latter as therapeutic lag. However, if you have neuronal reserve in a pathway, the arms and hands in this case, then you get a read-out in relation to anti-inflammatory effects much sooner. It is a great tragedy that the ASCEND study was not 3, or 4, years in duration. I am sure based on other insights this would have been sufficient to see an effect on lower limb function. Unfortunately, l ong trials in SPMS are a problem because of drop-outs so it not really feasible to do studies much beyond 2 years. To overcome this issue we need to focus on arm & hand function as the primary outcome, or after the analysis below sustained improvement.”
“What is important about this study is that the time course of disease improvement (early) and disease progression (late) must be due to different mechanisms. I suspect disease improvement is directly linked to switching off inflammation and reversing conduction block and allowing remyelination and axonal and synaptic plasticity to occur. These process occur over weeks to months and are well described in acute lesions, for example optic neuritis. The latter indicates that SPMS, even advanced SPMS, is characterised by focal inflammation. I therefore suspect SPMSers are still having relapses, or focal lesions, which are probably occurring below the detection threshold of the MRI. Dare I call these micro-relapses? In comparison, reducing delayed disability progression is the impact of anti-inflammatories, on preventing chronic axonal damage and with the resultant delayed fall-out of damaged axons over months to years.”
“The results of this ASCEND study are simply stunning and mean that progressive MS is a tractable problem. I don’t think the sustained improvement is due to neuro-restoration, but simply due to recovery of function of existing axons. We talk about developing new techniques and method for doing progressive trials, but I think we already have the toolbox at our disposal. All we need to do now is get on with doing as many SPMS and PPMS trials as possible with a focus on disease improvement (early) and delayed progression (late) with the primary outcome being upper limb function (#ThinkHand), over lower limb function, in MSers with more advanced MS (EDSS >= 6.0).”
“I sincerely hope all of you are as excited by this as I am. If Biogen don’t go to the regulators with this data then we the MS community need to start the discussion. Yes, I am aware that natalizumab is expensive and the cost-effectiveness of natalizumab in SPMS may not hold up to NICE, but natalizumab will eventually come off patent and hopefully cheap biosimilars will make it cost-effective. If I had SPMS I would want to be on natalizumab; I value my hand and arm function far too much.”
CoI: multiple
“The poster below is one of my ECTRIMS highlights. It has made me think differently about MS, in particular about the mechanisms behind the improvement in neurological function. In short if the natalizumab in SPMS trial (ASCEND study) had been designed with the primary outcome being sustained improvement in function then we would have had a drug available for SPMS. It is quite amazing given what ‘we think we know about SPMS’ that this study was positive. I thought that advanced SPMS was progressive with little room for recovery of neurological function. How wrong I was!”
“As you know the ASCEND trial was ‘negative’ in that it did not hit its primary outcome at 2-years, which was a composite loaded with lower limb function (EDSS and timed-25ft-walk or T25W). However, the trial was positive on the 9-HPT. In other words SPMSers on natalizumab have something to gain from natalizumab in relation to protecting arm and hand function. In fact natalizumab was so good in the ASCEND trial that it almost flat-lined upper limb function. Why the difference in outcomes between lower and upper limbs? I have made the argument many time before that if you have lost your reserve capacity in a particular system, which was the case in the lower limbs in this study (most subjects had an EDSS of >= 6.0) then it would take years to see a positive outcome. I have referred to the latter as therapeutic lag. However, if you have neuronal reserve in a pathway, the arms and hands in this case, then you get a read-out in relation to anti-inflammatory effects much sooner. It is a great tragedy that the ASCEND study was not 3, or 4, years in duration. I am sure based on other insights this would have been sufficient to see an effect on lower limb function. Unfortunately, l ong trials in SPMS are a problem because of drop-outs so it not really feasible to do studies much beyond 2 years. To overcome this issue we need to focus on arm & hand function as the primary outcome, or after the analysis below sustained improvement.”
“What is important about this study is that the time course of disease improvement (early) and disease progression (late) must be due to different mechanisms. I suspect disease improvement is directly linked to switching off inflammation and reversing conduction block and allowing remyelination and axonal and synaptic plasticity to occur. These process occur over weeks to months and are well described in acute lesions, for example optic neuritis. The latter indicates that SPMS, even advanced SPMS, is characterised by focal inflammation. I therefore suspect SPMSers are still having relapses, or focal lesions, which are probably occurring below the detection threshold of the MRI. Dare I call these micro-relapses? In comparison, reducing delayed disability progression is the impact of anti-inflammatories, on preventing chronic axonal damage and with the resultant delayed fall-out of damaged axons over months to years.”
“The results of this ASCEND study are simply stunning and mean that progressive MS is a tractable problem. I don’t think the sustained improvement is due to neuro-restoration, but simply due to recovery of function of existing axons. We talk about developing new techniques and method for doing progressive trials, but I think we already have the toolbox at our disposal. All we need to do now is get on with doing as many SPMS and PPMS trials as possible with a focus on disease improvement (early) and delayed progression (late) with the primary outcome being upper limb function (#ThinkHand), over lower limb function, in MSers with more advanced MS (EDSS >= 6.0).”
“I sincerely hope all of you are as excited by this as I am. If Biogen don’t go to the regulators with this data then we the MS community need to start the discussion. Yes, I am aware that natalizumab is expensive and the cost-effectiveness of natalizumab in SPMS may not hold up to NICE, but natalizumab will eventually come off patent and hopefully cheap biosimilars will make it cost-effective. If I had SPMS I would want to be on natalizumab; I value my hand and arm function far too much.”
‘Now that I can’t walk, my hands and arms have become my legs….’
a person with MS
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| Deb Steiner and Prof G at the poster at ECTRIMS! |
CoI: multiple
According to your post Natalizumab helps those in SPMS to preserve the hand function, but NICE will judge against its use on the grounds of cost-effeciveness. Will neuros in Barts start prescribing Natalizumab on patients with SPMS as off-label? Can these people get it prescribed on other hospitals if they pester their neuros? When will the patent of natalizumab expire?Are those with RRMS on Tysabri more likely to protect their arms/hands compared to those on other DMTs (and especially alemtuzumab)?
Will Barts prescribe….unlikely as NHS England will not re-emburse just like they have refused requests to use rituximab off-label.Will hand function be protected with other DMT…yes but fingolimod seems to be an odd-one out…why?
You see, if you get info from ProfG and you get the glass half full approach:-).Likewise if you look at the 9HPT the hand function in the ocrelizumab PPMS study was protected, likewise in CARE-II study P610 Singer et al. reported that Harzard ratio for benefit (improvement) in 9H-PT was 2.06 (1.06-5.48 95% PI) verses 1.26 (0.65-2.42) for T25F walk
I was on Tysabri for 3 years but came off it owing to being JC Virus positive. I'm in a wheelchair but had episodes of walking while on Tysabri. While on Tysabri I also had chronic upset stomachs so was offered Lemtrada. On stopping Tysabri I had an awful relapse which affected my hands which have continued to get progressively worse despite Lemtrada. Should/could I ask to go back on Tysabri or ….?Is there data on Ocrelizumab and PML?
So far, there has been no case of PML with Ocrelizumab (PERA I, OPERA II, ORATORIO study).
So far, there has been no case of PML wirth Ocrelizumab (OPERA I, OPERA II, ORATORIO study).
"CoI: multiple"And that's why I don't feel I can trust this 100%.
Honesty is the best policy.
Unfortunately there is nothing I can do about my conflicts! Let's hope we can repeat this study's finding with off-label cladribine. Would you trust the results then?
Are you wearing a Think Hand t-shirt?Tony
Yes, I am wearing a #ThinkHand T-shirt. I have a lot of spares so if you drop me an email with your size (S/M/L/XL) and address I will send you one in the post. First come, first served.
Does it have anything to do with OCB disappearance seen on natalizumab ?
Re: "Does it have anything to do with OCB disappearance seen on natalizumab ?" Not sure if the small case series of disappointing OCBs are a real finding or not. A larger German study did not confirm the earlier results. But I doubt it has anything to do with disappearing OCBs. The treatment effect is to quick. I am sure it due to anti-inflammatory effects of natalizumab.
Would you expect to see the same "sustained imptovement" in upper limb function if it were PPMS patients? Assuming they had similar (or even better) EDSS scores.Trying to understand if this is relevant only to individuals who went RRMS -> SPMS or if it is significant to those with PPMS.
Anon 2:25 – that is a very good question I think. A fundamental and crucial question.
Ocrelizumab did better in PPMS
This idea matches many anecdotal reports of those with progressive MS who have had non myelo HSCT
Glass half empty point of view. How many MS patients that are JCV + could even stay on Tysabri safely without risk of PML for over 2 years of treatment, let alone the 4-5 years that Dr. G would like to see? With Tysabri how many patients will be alive to exhibit this "therapeutic lag" hypothesis. Is there other medications that MS patients could use other than Tysabri, i.e. alemtuzumab, BG12, cladribine, ocrezulimab ??? What about HSCT with ablative vs. non-ablative therapy?
I have askd exactly the same question below but noone has answered it. People are talking excitedly about protection of existing functionality for those with SPMS, such as me. Is there nothing available for me and thousands of others in the same boat?
Re; "Is there other medications that MS patients could use other than Tysabri, i.e. alemtuzumab, BG12, cladribine, ocrezulimab?"What this study shows is that with a high-efficacy therapy such as natalizumab you can modify the course of SPMS. What we need to do is change a trial design to maximise the chances of getting a success with future trials. That is to focus on disability improvement and upper limb function. At present I can't recommend other drugs because we don't know if they will work in this situation which is why we need trials. We are in the process of designing a trial with off-label cladribine as a starter. But we are also lobbying industry to do the same; I see no reason why alemtuzumab, ocrelizumab, oral cladribine or daclizumab can't be tested using this paradigm. However, before Pharmacist does a large phase 3 trial they will need to be convinced the regulators (EMA & FDA) and the payers will accept a trial with these outcome and whether or onto they will need to do one or two trials. So at present we can't recommend any of these treatments as they are too expensive to prescribe off-label; the NHS and insurance companies will say no. We also want to manage expectations and these therapies are not going to reverse much disability to normal. In all likelihood their effect will modest and slow down progression.
Biogen states that the ASCeND trial is negative yet the 9 hpt was positive and the study was not designed properly……"up is down and down is up". "Would you tell me, please, which way I ought to go from here?""That depends a good deal on where you want to get to.""I don't much care where –""Then it doesn't matter which way you go.” ― Lewis Carroll, Alice in WonderlandHave we fallen into a rabbit hole? 🙂
Are you going to discuss the presentation on HSCT from Silesian Medical University, Katowice, Poland? It would be interesting to get your views on the scientific robustness of this paper and its findings and how it moves forward the discussions / or not of HSCT as a viable treatment / cure.
I am JC positive and was on the ASCEND trial. I do not know if I was on a placebo or not. It would be stupid for me to consider Tysabri even if it was available. I have noticed that ,y hands ar becoming clumsier, writing is very difficult and doing up shirt button is tricky. This has all developed in the last couple of years.Is therre another drug/treatmemt that would slow down or even stop the inevitable?
If I'm honest, I'm almost disturbed by this, because I see DMTs as very possibly being worse than the disease in my case – having slow moving progression.
The more I think about this though, the more excited I am that this is finally a way to find drugs that will work for *progression*, for PPMS. I can see that looking using mobility as an indicator is nonsensical, and that this will truly be a breakthrough in methodology in drug trials. (Although I wonder why no neurologist thought of this before???????)I am less excited by Ocrelizumab: Nasty long term side effects, wrecking ball approach, not working in everyone with PPMS even if you look at results in terms of hand function?
Will the community get behind natalizumab treatment in SPMS? I suspect not, we are a lost and forgotten cause.
Re: "Will the community get behind natalizumab treatment in SPMS?"Maybe; we would need to work on the community. Not many people I know buy into the length-dependent axonopathy and therapeutic lag hypotheses. In addition, there was a disconnect between MSers and Neurologists on whether or not treatments work in SPMS.
Re: "…we are a lost and forgotten cause."I may be glass-half-full kind of person, but the whole #ThinkHand campaign is to address a massive unmet need and to get effect treatments into the clinic for both SPMSers and PPMSers. I know you are inpatient, but things are happening.