ThinkSpeak & ResearchSpeak: my top highlight from the AAN 2016 meeting in Vancouver

The ASCEND SPMS trial demonstrates that SPMS is not an intractable problem #ThinkSpeak #ResearchSpeak #MSBlog #MSResearch #AAN2016

People with SPMS now have hope #ThinkSpeak #ResearchSpeak #MSBlog #MSResearch #AAN2016

My top highlight for the AAN 2016 are the ASCEND Trial results #AAN2016

"Most commentators have dismissed the natalizumab in SPMS trial, or ASCEND trial, as being negative and have simply moved on. 

One person said to me: 'SPMS is an intractable problem and it is best to prevent it by early effective treatment’. Another said: 'What did you expect, the ASCEND is just another negative SPMS trial, which could easily have been predicted from our experience with the interferon trials.' How cynical and sad? These attitudes entrench the concept of the therapeutic window in MS and perpetuate the concept that it is futile to try and develop treatments for SPMS. I disagree with both of these positions and prepared to go out on a limb and hypothesise that the therapeutic window remains open throughout the course of MS and it is not futile to try an develop treatments for SPMS. We have to give people with MS hope. In my opinion the ASCEND Trial was clearly positive; although the study did not hit the desired primary outcome natalizumab did show an effect in virtually flattening loss of upper limb function. Surely a treatment that protects upper limb function in people with SPMS is worth exploring further? To quote one SPMSer: 'Now that I am in a wheelchair my hands and arms have become my legs’.

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What is galling is the ORATORIO trial of ocrelizumab in PPMS was positive. Is ocrelizumab really superior to natalizumab? Is PPMS that different to SPMS? I would argue no on both accounts. The differences between the ASCEND and ORATORIO trials can be explained on differences in the study populations. The ASCEND SPMS population was older and more disabled; over 60% of study subjects had an EDSS of 6.0 or 6.5. In other words they had lost most meaningful reserve capacity in the motor system to their legs. We know from other studies that at a disability level of EDSS of 6.0 (unilateral support) or 6.5 (bilateral support) the EDSS is not a very good outcome measure over 2 years; most MSers with this level of disability spend many years at these levels before progressing to a higher level of disability. In measurement speak we refer to this as the ceiling effect of the EDSS. In comparison over 60% of PPMSers in the ORATORIO study had an EDSS of less than 6.0 and hence were at a level of disability on the EDSS scale that is more likely to move. In addition, with a disability below EDSS 6.0 there is more reserve capacity in the motor system to allow recovery of function and get a read-out in a two year period. In other words at lower levels of disability there is less therapeutic lag.

For the last 2-3 years I have been discussing two concepts, or hypotheses, on this blog, i.e. therapeutic lag and the length-dependency. The results of these two studies, with other evidence - new and old - strongly support both these related hypotheses. Therapeutic lag states that the more reserve that is lost in a specific pathway the longer it will take to see a treatment effect in relation to therapies that are targeting MS specific mechanisms. This is why the ORATORIO trial was positive on both the EDSS and timed-25-foot walk (T25FW), and the ASCEND trial was negative on both these outcome measures. I would predict that if the ASCEND trial had been longer in duration then it may have been positive on both of these outcomes, in particular the T25FW which is more sensitive to change than the EDSS. Unfortunately, the ASCEND trial did not allow for therapeutic lag. If these hypotheses are correct the treatment effect of ocrelizumab should be greatest in comparison to placebo in the ORATORIO trial in relation to upper limb function, which is assessed using the 9-hole peg test. We will have to wait for more detailed analyses from the ORATORIO trial to be published to see if this is the case.

So what have we learnt from the ASCEND trial?

  1. That non-relapsing SPMS is a tractable problem; if we focus on the relevant outcomes, i.e. neuronal systems that have sufficient reserve capacity to demonstrate a treatment effect using responsive outcome measures such as the 9HPT and the ABILHAND we have a chance of a positive trial. The ABILHAND is a validated patient-related outcome measure of hand and upper limb function. 
  2. If we are going to continue to have to use the EDSS as an outcome measure we are either going to have to study an earlier population, similar to the ORATORIO study population, or do longer studies to allow for therapeutic lag. 
  3. In my opinion we need to ditch the EDSS as a primary outcome measure in progressive MS trials. For those of us old enough to remember we have seen evidence for these arguments in relation to the interferon in SPMS trials. The European interferon-beta-1b SPMS trial was positive when the North American study was negative; the former was in a younger less disabled population, whereas the latter was older and more disabled. 
  4. If we are going to do studies in more advanced MS then we need to focus our attention on neuronal systems with functional reserve, for example upper limb and bulbar function (speech and swallowing). For this to occur we will need to bring the regulators (EMA and FDA) on board. I think this is possible and is now urgent. 
  5. I suspect that to have a realistic chance to modify the non-relapsing progressive phase of MS we will need to use highly-effective DMTs. I am not surprised that both ocrelizumab and natalizumab have produced positive trial results in these populations; please note my emphasis on positive.  Because of this I have been lobbing Pharma to do trials in advanced progressive MS (both PPMS and SPMS combined) with the highly effective DMTs, i.e. alemtuzumab, ocrelizumab, daclizumab, ofatumumab and cladribine. Let's see who is brave enough to take on the challenge. If Pharma won't do it we will. 

Some caveats. The cynic in me worries more about the payers than the regulators. The cost effectiveness calculations in relation to DMTs are based on the cost of the treatment versus the savings to the individual and society. Once a person with MS has lost their mobility they have already accrued a large amount of personal and societal costs. These include both direct medical cost and indirect costs for example loss of employment. The sad thing once a person becomes unemployment their worth to society drops. If this is the case then the payers, for example NICE, may judge the cost-effectiveness of DMTs in more advanced MS to be less favourable; in other words expensive high-cost drugs such as natalizumab and ocrelizumab may not be cost-effective in more advanced MS compared to early MS when preservation of function will save society more money. This is one reason why Pharma are reluctant to take on the risk and develop drugs for more advanced progressive MS. A potential way to counter this is to allow Pharma and payers to agree to a differential payment scale; the more disabled a person with MS is the less the company is able to charge for their drug. This may sound crazy but it makes a lot of sense to me; it would force pharma to move to an outcomes based remuneration system. Under this system payers will get better value for money and pwMS will get treatments that work. This will allow us to move away from a fixed-pricing system to a value-based pricing system. We seem to be getting used this in many other sectors, surge pricing systems are used by the airlines, software industry and Uber. If you have used Uber you will know all about surge pricing. I can see a world where the same agent is more expensive when used in early MS and as the patient becomes more disabled the price for the drug is less. The question is the NHS and the Pharmaceutical sector ready for valued-based pricing? I think so this is already being explored in oncology. Why should the NHS, or individual, pay for something that doesn’t work? On the other hand why should we deny people with progressive MS drug X because it is considered to be not cost-effective at their stage of the disease ?

You can see that I am all fired-up from the AAN with as many ideas whizzing around my head as minutes in the day! Attending conferences provides thinking, talking, networking and downtime. This AAN was no exception. I would like to conclude this post with a huge thank you to Biogen for having the balls to do the ASCEND study and for the SPMSers for volunteering to take part in the study. Without this study we wouldn't have these insights.

Finally, a appreciative thank you to a well-meaning and generous Pharma executive who gave up his first-class upgrade to try and help me get a good nights sleep. When I was sitting in the BA lounge waiting to board my return flight from Vancouver a senior Pharma Executive, who I know well, came over to chat to me. When he heard I was flying economy+ back to London he tried to get me a business class upgrade. He was called to the BA desk for a first-class upgrade and turned it down by asking BA if they could upgrade me instead. They said they would try. However, when we got to board we both had our originally allocated seats. I am grateful that someone would try give up the comfort of a first class upgrade to try help me get a good nights sleep. However, I would prefer him to lobby his company to do a SPMS trial based on the insights of the ASCEND study."

CoI: multiple

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