Saturday, 20 August 2016

ResearchSpeak: fighting over the crumbs

How big is the DMT pie? Is there space for 'Me Toos'? #ResearchSpeak #MSBlog #MSResearch

"As the MS DMT market matures the appearance of 'Me Too' drugs will increase. The phase 2 study below is of a new S1P modulator called Amiselimod. This is one of many 'Me Too' S1P-modulators in development hoping to get to market and carve out a slice of the $20-billion+ MS market and/or to extend into other disease areas. Some of the other S1P-modulators in development are Siponimod (Novartis), Ozanimod (Celgene), Ponesimod (Actelion), Ceralifimod (Ono), MT-1303 (Biogen-Mitsubishi), etc. An important issue in the MS space is that fingolimod is due to come off-patent soon and there is little doubt the price of fingolimod will come down substantially. I would predict that generic fingolimod will be over 70% cheaper than the innovator formulation (Gilenya). Generic fingolimod will have a major impact on the market, which is becoming increasingly price sensitive. Depending how generic fingolimod is used it may reduce the size of the DMT market by 40%; this means the 'Mee Toos' will left fighting over the crumbs."

"The one issue we have in Europe is that fingolimod is essentially a 2nd-line drug and it only recently had its label changed to treat rapidly-evolving severe (RES) MS as a first-line option. With natalizumab licensed for RES, and ocrelizumab due to be licensed, I doubt fingolimod will be used much as a 1st-line agent for patients with RES-MS. I also doubt Novartis has any incentive to get fingolimod a 1st-line label in Europe now that they have ofatumumab (anti-CD20) in development. So it will be left to us, the MS community, to explore ways to get the label of fingolimod changed in Europe."

"Of the other S1P modulators in development Spinonimod is the closest to market; the phase 3 results of the large SPMS trial is due to report. Please note that Siponimod is being developed for SPMS, and not RRMS, therefore Siponimod is hoping to expand the pie. This would be very good news for SPMSers. The others S1P modulators may have a space if the can improve on fingolimod's safety profile, i.e. fewer cardiac side effects, and are able to deliver more efficacy than fingolimod. Based on their pharmacokinetic & pharmacodynamic profiles and early phase 2 results some of these agents promise to do just this. However, the main problem of S1P-modulators going forward will be long-term immunosuppression, with opportunistic infections and secondary malignancies, being the main concern."

"Personally, I remain optimistic that a Black Swan will deliver a cure, or MS prevention, then the pie will become very small with even fewer crumbs."

How big is the MS pie?

Kappos et al. Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurology 2016 (Epub). 


Background: Patients with multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system with autoimmune pathogenesis, have shown partial response to a number of immunomodulating treatments, but the search for more effective, safe, and convenient therapeutic options continues. Amiselimod is an oral selective modulator of sphingosine 1-phosphate 1 (S1P1) receptor, which is being developed for the treatment of various autoimmune-mediated diseases. We assessed the safety and efficacy of amiselimod in patients with relapsing– remitting multiple sclerosis.


Methods: In this double-blind phase 2 trial, patients aged 18–60 years with active relapsing–remitting multiple sclerosis from 84 centres in Europe and Canada were randomly assigned (1:1:1:1) with an interactive web-response system to receive once daily oral amiselimod 0·1 mg, 0·2 mg, 0·4 mg, or placebo for 24 weeks. All study personnel, site personnel, investigators, and patients were masked to the treatment assignment during the study. The primary endpoint was the total number of gadolinium-enhanced T1-weighted lesions on monthly brain MRI scans from weeks 8 to 24. Analysis was done on the predefined evaluable population (all randomised patients who did not have any major protocol deviations, completed 24 weeks of treatment as planned, and had at least three valid post-dose MRI scans). This trial is registered with ClinicalTrials.gov, number NCT01742052.

Findings: Between Jan 31, 2013, and Dec 24, 2013, 536 patients were screened and 415 patients randomly assigned to amiselimod 0·1 mg (n=105), 0·2 mg (n=103), 0·4 mg (n=104), or placebo (n=103). The median total number of gadolinium-enhanced T1-weighted lesions from weeks 8 to 24 did not differ between the amiselimod 0·1 mg and placebo groups (median 1·6 lesions [range 0–132] in the placebo group vs 2·0 [0–105] in the 0·1 mg group [median difference 0·0, 95% CI −1·0 to 0·0, p=0·7517]), but was significantly lower in the two higher amiselimod dose groups than in the placebo group (0·0 lesions [range 0–35] in the 0·2 mg group [median difference vs placebo −1·0, 95% CI −1·0 to 0·0, p=0·0021] and 0·0 [range 0–30] in the 0·4 mg group [–1·0, −1·2 to 0·0, p=0·0003]). The estimated incident rate ratio compared with placebo was dose-dependently decreased with amiselimod (0·1 mg 0·53 [95% CI 0·33–0·85; p=0·0079], 0·2 mg 0·39 [95% CI 0·24–0·63; p=0·0001], and 0·4 mg 0·23 [95% CI 0·14–0·38; p<0·0001]). The incidence of treatment-emergent adverse events, including infections and cardiac disorders, were similar in the amiselimod treatment groups (59 [56%] of 105 patients in the 0·1 mg group, 69 [67%] of 103 in the 0·2 mg group, and 58 [56%] of 104 in the 0·4 mg group) to the incidence in the placebo group (66 [64%] of 103 patients); the most common treatment-emergent adverse events were headache (ten [10%], ten [10%], and ten [10%] vs four [4%]) and nasopharyngitis (nine [9%], seven [7%], ten [10%] vs eight [8%]). No serious treatment-emergent adverse event was reported for more than one patient in any group and no clinically significant heart rate reduction was observed at any amiselimod dose.

Interpretation: Amiselimod 0·2 mg and 0·4 mg significantly reduced the total number of gadolinium-enhanced T1-weighted lesions. The safety and efficacy profiles of amiselimod suggest that this S1P1 receptor modulator is a new potential treatment in multiple sclerosis and potentially other immune-mediated inflammatory diseases and deserves further investigation.

Funding: Mitsubishi Tanabe Pharma Corporation.

CoI: multiple

22 comments:

  1. Costing may drop in some areas of the world. Question is will it elsewhere as well. Glatopa (Copaxone Generic) has little in the way of cost savings at least to insurers here in the colonies.

    I just read a rather interesting article as the Kaiser Foundation (USA -> http://kff.org/medicaid/issue-brief/medicaids-most-costly-outpatient-drugs/)

    Indeed there are buckets of medications in the pipeline. I wonder if Ocrelizumab should it pan out as predicted result in many of the pipeline meds discontinuing exploration?

    I sorta think Australia is rather ahead of curve as research operations can be granted levels of access to real people as compassionate care (responsibly).

    Aka: Innate Immunotherapeutics SPMS candidate.

    I tend also think medicine like HSCT should have similar access BUT under terms of open access. Experimental medical procedures need be heavily monitored and affordably accessible along with proper vetting of prospect volunteer patients.

    SURELY a better system need be implemented and can be that works for all parties and removes the prospects of over-hype. MS is not the only disease where it occurs. Open access would allow for better vetting of the procedures and research as well as hopefully raise levels of professional care in such instances globally?

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  2. "I also doubt Novartis has any incentive to get fingolimod a 1st-line label in Europe now that they have ofatumumab (anti-CD20) in development. So it will be left to us, the MS community, to explore ways to get the label of fingolimod changed in Europe."
    Wouldn’t you agree it is highly unlikely “the MS community” (who do mean here anyway – pwMS, Big Pharma, neurologists with an interest in MS, MS nurses…? – They are not the same!) is going to change a label given these are being applied for by companies and awarded by regulators, who are – at least in Europe - being paid by exactly the same companies? Unless there is an issue with potential to cause outrage on a broader scale, their only response will be to shareholders’, but not public pressure. Remember Sanofi-Genzyme’s suspension of Alemtuzumab prior to the EMA license? This caused a stir in a tea cup followed by business as usual. The only way I can see is using Fingolimod off label, for example by redefining MRI activity as relapses. One of my patients with PPMS had an excellent response to the drug.

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    1. We are on the case already. We would also like Natalizumab to be 1st-line in JCV-negative patients. The fact that Alemtuzumab and Daclizumab both have first-line labels shows you how things have changed.

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    2. Fingolimod with PPMS? Really? Going against the grain a bit there?

      https://www.youtube.com/watch?v=EzM1NbZ-7nU#action=share

      http://www.msdiscovery.org/news/new_findings/27009-lessons-fingolimod-primary-progressive-multiple-sclerosis

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    3. ? So enlightening, helpful, pleasant and professional. As always.

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    4. ? = I don't understand what you are what you saying/asking

      Professional as ever taking the time to read when i'm away

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  3. Why would generic fingolimod be much cheaper than original? After all, price of generic glatiramer acetate is only 15% less. Why would a generic version of an oral MS and more effective MS therapy cost less?

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    1. RE: "Why would generic fingolimod be much cheaper than original?"

      Fingolimod is a small molecule drug and therefore it will be easier for generic manufacturers to enter the market. GA is almost like a biological and hence difficult to manufacture, this is why the other glatiramoids are not that much cheaper. The small molecule vs. biological issue is something that industry has not missed and explains why there are so many biologicals in development. Just look at the profits that insulin, the first biological, still makes for Pharma.

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  4. May I ask: Why are you optimistic about a black swan? I know that we learn more every day and therefore a black swan becomes more likely.

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    1. Re: "Why are you optimistic about a black swan?"

      Because I think we have already found the cause of MS. i.e. EBV. All we now need is an effective vaccine and an effective anti-viral agent targeting EBV; I suspect a small molecule anti-viral may do the job as well, or better, than an anti-CD20s and other B-cell depleters.

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    2. Are any of the current retrovirals working on EBV? I want to believe it might be as easy as finding a cocktail from the existing antivirals but the studies done towards that end have mostly been a bust.

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    3. A black swan for progressive MS too??? I've asked this question before, and didn't get an answer. I suppose there isn't one.

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  5. Is their an accepted hierachy of DMT that considers both safety and effectivness? If so where will new drugs such as Ocrelizumab sit? It seems like that is deemed the great white hope for multiple types of the diease.

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    1. For me, with PPMS, not really - the reduction in progression is only modest, will only occur in some people, and the drug carries significant risk of malignancy.

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    2. (To me, Ocrelizumab seems more of a great white elephant than a great white hope.)

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    3. Scottish Clive. The unhelpful answer to your question is officially Ocrelizumab is better than interferons. https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline/ocrelizumab

      i think a more practical answer to your query (and i stand ready to be corrected on this): at this early stage, ocrelizumab results seem similar to lemtrada, if not better, but it's too early to tell. in any case, it appears ocrelizumab does not suffer to the same extent from secondary autoimmunity.

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  6. I wish fingo had kept working for me. Next to alemtuzumab's two-and-done promise, popping that pill every morning was super convenient.

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  7. I'm super super super grumpy that this was a placebo group study. What are people with MS - pawns? In 2013 - years after gilenya and tysabri (and even tecfidera) received approval. there should have been no need for a placebo group that I see.

    103 people who should have been on a DMT but, at least for 24 weeks, weren't. 103 people who either had a relapse in the last 12 months or an enhancing lesion 3 months before screening or 2 relapses in the last 24 months AND an enhancing lesion in the last 12 months had treatment withheld from them in the name of (questionable) science.

    in the day when we had more than on crumb of this friggin pie - we had the interferons, tysabri, gilenya, tecfidera and lemtrada was in the pipeworks.

    Why isn't anyone more indignant that 103 people with MS were in this placebo group?

    A better question yet: under which circumstances would you, as a researcher/clinician with a close relative with RRMS recommend to that relative to agree to a trial where they are placed on a placebo?

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    1. Maybe people need to stop volunteering for placebo controlled DMT trials.
      then the trials would not recruit and so the practice would stop.

      However what does it say about the regulators and the trial investigators? How do they make the justification. It is cleaner science and so easier to see effects, specially as the regulators sometimes have problems seeing benefits in trials.

      The 130 getting nothing are on a trial and so they would do better than being trial and maybe they get drug in the end.

      Should they have done a non-inferiority trial against fingolimod (but this could be a marketing disaster if it was worse and it would have to be second line so harder to recruit) but they would have to pay for the drug and this would cost 130 x $50,000 plus so an extra £65,000,000 to compete with the big boys. Until there is a cheap alternative I suspect the placebo will not go away. But if there is a cheap alternative then companies won't invest in new drugs in MS.

      However, it is interesting that they do not do the study in Japan or the USA and clearly do studies in places were people do not have access to drugs or cannot afford them. The sites were

      Brussels, Sofia, Edmonton, Zagreb, Vantaa, Berlin, Budapest, Roma, Kaunas, Katowice, Moscow, Belgrade, Madrid, Basel, Istanbul, Kiev,
      London. (Were we one?)

      The International MS Societies appear to take the view that people in less affluent regions should not be second class citizens and take unlicenced cheap drugs....verses getting nothing?

      Otherwise they may be interested in developing the evidence base for azethioprine or cladribine However do they campaign against placebo control where people who are surely second class citizens :-(

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  8. Dear Bozo
    Your comment was put in spam by someone perhaps to limit a rant.


    To clarity, it is the regulators,ethics panels and neuros who decide on the value of drug verses nothing and neuros need the backbone to decide when to draw the line. Some people slip through drug availability cracks in the system and then they like people who are first or second class citizens in the eyes of pharma make a risk benefit analysis when deciding to participate in studies.

    A trial of 103 of placebo verse drug is unlikely to be n=103 of drug verses active comparator is likely to be more people needed, someone can do the power calculation.

    Drug cost $25,000 x 103 = ~$3,000,000 for 6 months trial if it is this not fingolimod as comparator it would make the trial difficult to blind.

    However, you will have to pay the going rate of the drug if you are a company or you are not giving current care, such as via an NIHR application where the drug cost of the comparator arm would be covered by NHS

    Therefore how many phase II do we see test drug against a comparator...very, very few (e.g. Alemtuzumab verse beta interferon)

    Academics can't afford to do a test verses comparator drug and so they use placebo or do not do DMT studies anymore.

    Is phase III what happens depends on the regulators and the companies arguments.

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