Thursday, 22 October 2015

NewsSpeak: natalizumab SPMS trial is negative

We need to learn why the ASCEND trial was negative; we owe it SPMSers! #NewsSpeak #MSBlog #MSResearch

"Biogen have just made a press release stating that the natalizumab in SPMS or ASCEND trial was negative. I predicted based on the length-dependent axonopathy hypothesis that this trial would be negative in relation to lower limb function, but not upper limb function. This prediction was based on the short duration of this trial (24 months)."

"I am very interested in doing a post-hoc analysis of this study. Could it be positive if early lower limb progressions (EDSS and timed-25ft walk progressions within the first 12 months), which are pre-programmed by previous damage, are excluded from the analysis; i.e. these study subjects are kept in the study looking for second progressions? However, the limiting factor is this study was its duration; it was simply too short. It is a great pity it was not an adaptive, event-driven, stydy that ran for 36+ months. I suspect the open cheque-book associated with these event-driven trials makes it too expensive and risky for Pharma."

"I really feel for all the SPMSers who were hoping for this study to be positive. The fact that this study delayed disease progression in the upper limbs is excellent news. It means inflammation is alive and kicking in the SPMS phase of  the disease and that it is worthwhile continuing to look for effective treatments to target this phase of the disease. Don't forget upper limb function is as important, if not more important than lower limb function, to preserve if you have SP or PPMS."

"I would like to thank Biogen for taking on the challenge of SPMS. I hope your next SPMS trial is designed differently to learn the lessons of the ASCEND trial." 


.... The Phase 3 ASCEND study investigating natalizumab in the treatment of secondary progressive multiple sclerosis (SPMS) did not achieve its primary and secondary endpoints...


.... Given the challenges of treating this advanced stage of MS, these results underscore the importance of treatment early in the course of disease with effective disease-modifying therapies before a patient advances to SPMS....

.... ASCEND evaluated the efficacy and safety of natalizumab to slow the accumulation of disability progression unrelated to relapse in SPMS patients, an unmet medical need. The majority of study participants had EDSS scores of 6.0 to 6.5 (walking aid required) and were non-relapsing for two years prior to enrollment in the study. The study’s composite primary endpoint evaluated the percentage of patients whose disability had progressed on one or more of three disability measurements comprising the composite endpoint.....


..... Natalizumab demonstrated a statistically significant effect on upper limb function (one of the three components of the primary composite endpoint) unrelated to relapses. Consistent with the established effects of natalizumab in relapsing multiple sclerosis, analyses of exploratory endpoints suggest that some patients received a benefit from treatment, including reduction of relapses and new MRI lesions .....


..... SPMS is characterized by ongoing nerve damage or loss and patients experience disability progression with increasingly less frequent relapses. Despite extensive clinical research, treatment options for patients with SPMS are extremely limited and none have demonstrated efficacy in slowing the progression of disability unrelated to relapse..... 


CoI: multiple

24 comments:

  1. It's sad that the results of the trials in progressive MS depend on trial design to a much greater extend than the actual efficacy of the drug. No meaningful comparison of efficacy of different medications is possible. Unfortunately, it also means that the efficacy of apparently working medications (such as ocrelizumab vs. rituximab) is low, otherwise the effects of treatment would have been dramatic, and obvious regardless of trial design.

    ReplyDelete
  2. This study also looked at brain atrophy changes. I assume since nothing was mentioned this is negative also. This being the case we can conclude Tysabri can no longer be considered a "highly effective" therapy.

    If not, I would be interested in why you disagree.

    ReplyDelete
    Replies
    1. Highly effective at reducing/stopping relapses, not it appears at stopping progression but I need to know the details of the study before I can really make any definite conclusion. Does early treatment with natiluzumab during RRMS delay progression for instance.

      Delete
    2. and how do think you can find out that from this study?

      Delete
    3. Not from this study but long-term follow up data of pwRRMS who have been treated with natiluzumab to see if they progress to SPMS. In this study it'll be useful to see just at what stage they were given natiluzumab ie was their SPMS too far advanced for natiluzumab to make any meaningful difference or as Prof G says was the duration of study simply too short?

      Delete
    4. "long-term follow up data of pwRRMS who have been treated with natiluzumab to see if they progress to SPMS."

      Do you have data on this?

      I am told that PH IIIb RRMS participants have progressed to SPMS now despite compliance with the drug.

      Delete
    5. "The majority of study participants had EDSS scores of 6.0 to 6.5 (walking aid required) and were non-relapsing for two years prior to enrollment in the study."

      Ah, just as the (apparently) failed CUPID study, the EDSS score of the participants is too high to show any meaningful effect in 2 years. As the CUPID study showed you need lower EDSS scores to show a drug effect in the time course studied.
      http://www.ncbi.nlm.nih.gov/pubmed/25895527

      Delete
    6. Take home message, yet another crappy trial design but that said all our previous work has suggested this approach would not work anyway (if the clinicians/pharma bods bothered to read them, that is).

      Delete
    7. "I am told that PH IIIb RRMS participants have progressed to SPMS now despite compliance with the drug. "
      Were you told by one of the STRATA PIs?

      Delete
  3. What does this study say regarding the role of lymphocyte trafficking into the CNS and progression? Do other cells in the CNS (microglia and astrocytes) take center stage in the search for SPMS therapies?

    ReplyDelete
    Replies
    1. I thought the same Steve S. But beyond the macrophages and microglia maybe B cells "still want to say something" in SPMS ...

      Delete
    2. I think the role of activated microglia in progression in MS is of huge importance, as it seems to be in more and more neurodegenerative conditions.

      Delete
  4. Good news on progression delay if not on retroactive fix. So in the absence of anything else I'd be happy to stay on the drug.

    ReplyDelete
    Replies
    1. What other options do you have?

      Delete
    2. Well none obvs. But there is still some positive news to take out of this and hopefully scientists can build on that

      Delete
  5. Does anyone know if SPMS quickens and disability suddenly becomes worse without a relapse?

    ReplyDelete
  6. I've been on the Ascend trial for around 32 months & have noticed absolutely no progression in that time.
    I'd be more than happy to stay on the drug too.

    ReplyDelete
  7. Not sure if you're the same Anonymous as the previous Anonymous but yes, I agree.

    ReplyDelete
  8. Why is Biogen and other Pharma not using combination treatments or sequential treatments?

    ReplyDelete
    Replies
    1. Indifference to MSers needs, Greed and Accountants...so that’s greed:-(

      So first up The cynic comes out. Sequential treatments. They are doing that already.

      Buy avonex…fail, buy tecfidera….fail, buy natalizumab…fail or your 2 years are up buy daclizumab…..fail buy, anti-Lingo-1 which will have become licenced by the time you've worked through the drugs before.:-(

      So that seems like sequential to me. Buy Biogen Buy Biogen buy Biogen:-) or and if you are buying ocrelizumab… you are also buying Biogen (Whilst it is a Roche product developed by Genentec, Biogen was involved in its development so Biogen will double digit royalties on US sales of ocrelizumab).

      If we had an induction treatment then a neuroprotection sound pretty sensible to me but oops we haven’t got any neuroprotectives yet….Why not? ……Accountants again.

      Because we are too busy making money out of relapsing MS, too busy to make a neuroprotectant. Who is going to pay for two expensive drugs, so best wait until one goes out of patent and then the price will drop because of competition?

      Dam I forgot it is a cartel and so there is no price competition, Oh and I forgot we all make biologicals and when their patent expires the generic biologicals are only a few percent less and they can rely on brand loyalty as you wouldn’t pay more for cardboard would you?

      But when patents on small molecule expire and their price drops maybe expensive neuroprotectants/repair agents will appear

      Next up they could put one DMT on top of another. Beta plus teriflunomide does this equal natalizumab or does this mean one low efficacy treatment twice the cost and side effect.If it was more effective would the risk of PML be higher. Quite possible but if they did have different mechanisms there could be additive effects.

      The only way is to try it but would you want and pill and an injection. Surely you would want a pill and a pill . Teriflunomide plus gilenya but now you have genzyme and novartis would they work together to share the spoils or would you prefer to have the two drugs in from the same commpany. Why would Biogen want to give money to Novartis if it can have it all to itself.

      Ideally it would be a pick and mix of their own company products

      However to answer your question seriously combinations of treatments are the future seriously. This the way it will be ,but the big problem is the lack of pipeline. All the companies have are variations of the same product and what we need is alternatives like neuroprotection and repair agents but there isn’t a pipeline ready for prime time. However I believe companies have protection and repair agents in their portfolios, but they will need to test them in MS. However will they do the sensible thing and layer on top of a DMT or will they try a single drug. In progressive MS they will probably try a single drug but for RRMS they will layer on top of the other. However if drugs could be repurposed they could be ready for prime time and they could dig up the old drug portfolio.

      We will only know when they do phase II and III as that’s when pharma shows its hands up to that point it’s all in the accountants hands

      Delete
  9. So it appears the only thing shown to be efficacious (albeit nominally) in SPMS is concentrated Biotin.

    ReplyDelete
  10. Replies
    1. First thing licencing for rrms. We have to see how they approve for ppms or if they approve.

      Delete
  11. "I am told that PH IIIb RRMS participants have progressed to SPMS now despite compliance with the drug."

    My wife went bowling last night and only got two strikes but it is just amazing that she is a five-step bowler who still plays and enjoys the game. She entered the Phase 3 natalizumab study in March of 2002 and received 300mg dose (unblinded). Counting the 33 doses received during trial, 5 more after FDA approval and over 120 after re-introduction she has received approximately 160 total infusions with no new lesions and no progression, except during the time Tysabri was off-market. She was JCV + from the first test years ago and has been on dose extension for the last two, approx.

    Doubtless there have been those who were in PH 3 trial who entered SPMS but not all, as my wife clearly proves. The great tragedy is others who could be suffering far less from the effects of MS had they the opportunity to get a highly effective med earlier and had the persistence to stay with it in spite of unbalanced fear-mongering about PML. I say unbalanced because PML concerns are rarely balanced with MS concerns... the horrific progression which can be observed on less effective treatments, or no treatment at all.

    Takes a neurologist with true grit, also, who will stick with a JCV+ Tysabri patient who understands and accepts the risk of PML. Many patients don't even get the chance to choose; essentially, they get bullied off the treatment. Too much risk for the doctor, not the patient. A PML case would take up too much of a doctor's time, I suppose.

    Generally speaking, most people realize they won't exit the world alive and well. And specifically, MSers accept that reality sooner than most. Little wonder they accept more risk to enjoy better health during the brevity of years they recognize.

    A drug failing trial is disappointing but if a drug fails because of trial design it is a truly a tragedy, never more so when there is no viable alternative.

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.