Thursday, 19 November 2015

ClinicSpeak: spreading hope

The ocrelizumab ORATORIO results give hope to PPMSers #MSBlog #MSResearch #ClinicSpeak

"Earlier this week I made the diagnosis of primary progressive MS (PPMS) in one of my patients. This is the first time I have done so since the ECTRIMS meeting in Barcelona where the ocrelizumab PPMS trial (ORATORIO Trial) results were made public. What a difference this made! For the first time I was able to offer someone with PPMS hope. I countered the bad news of having just been given a diagnosis of PPMS with the news that for the first time a treatment had been shown to slow down the acquisition of disability in PPMS. This was an uplifting experience for all of us involved; for the first time PPMS has become a tractable disease. We shouldn't underestimate the effect of good news and being able to do something positive; it affects on our body language, our mood, the way we present ourselves, in short it gives hope." 

"The downside of this news is that in reality ocrelizumab will only be available, realistically, under the NHS in approximately 2 years time. The latter is assuming it clears EMA and NICE hurdles. The NICE hurdle is important for PPMSers in the UK; we are only allowed to prescribe DMTs that are shown to be cost-effective. NICE is pretty effective at driving a hard bargain with Pharma and explains why the cost of DMTs in the UK are probably the lowest in the developed world. Costs and access to ocrelizumab aside, could you imagine being diagnosed with PPMS, you are still mobile (able to walk ~100 m) and your neurologists tells you that you will have to wait 2 years to see if you may be eligible for the drug? Two years is a long time in the life of someone with PPMS; in 2 years their disability could progress to a stage when they need to use a wheelchair. The latter may make them ineligible for ocrelizumab. What should I do? Should I prescribe rituximab off-label? At least we have a reasonably robust evidence-base now to use rituximab in PPMS. Unfortunately, as rituximab is a high-cost drug we would need to get NHS England permission. NHS England have stopped us using rituximab in this setting."

"What I ended up doing is putting this patient forward for the laquinimod PPMS, or ARPEGGIO, study (see below). Ocrelizumab is not going to be enough on its own to treat PPMS, we will almost certainly need to combine it with a neuroprotective treatment in the future. Based on preclinical, and clinical, data laquinimod is the one neuroprotective drug we have in development that is likely to get through the pipeline first."


A Phase 2 Clinical Study in Subjects With Primary Progressive Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of Two Oral Doses of Laquinimod Either of 0.6 mg/Day or 1.5mg/Day (Experimental Drug) as Compared to Placebo

ClinicalTrials.gov Identifier: NCT02284568
Ages Eligible for Study: 25 Years to 55 Years
Genders Eligible for Study: Both

Inclusion Criteria:
  1. Patients must have a confirmed and documented PPMS diagnosis as defined by the 2010 Revised McDonald criteria
  2. Baseline magnetic resonance imaging (MRI) showing lesions consistent with PPMS in either or both brain and spinal cord
  3. Patients must have an Expanded Disability Status Scale (EDSS) score of 3 to 6.5, inclusive, at both screening and baseline visits
  4. Documented evidence of clinical disability progression in the 2 years prior to screening.
  5. Functional System Score (FSS) of > or equal 2 for the pyramidal system or gait impairment due to lower extremity dysfunction
  6. Patients must be between 25 to 55 years of age, inclusive
  7. Women of child-bearing potential must practice an acceptable method of birth control for 30 days before taking the study drug, and 2 acceptable methods of birth control during all study duration and until 30 days after the last dose of treatment is administered.
  8. Patients must sign and date a written informed consent prior to entering the study.
  9. Patients must be willing and able to comply with the protocol requirements for the duration of the study.
Exclusion Criteria:
  1. Patients with history of any multiple sclerosis (MS) exacerbations or relapses, including any episodes of optic neuritis.
  2. Progressive neurological disorder other than PPMS.
  3. Any MRI record showing presence of cervical cord compression.
  4. Baseline MRI showing other findings (including lesions that are atypical for PPMS) that may explain the clinical signs and symptoms.
  5. Relevant history of vitamin B12 deficiency.
  6. Positive human T-lymphotropic virus Type I and II (HTLV-I/II) serology.
  7. Use of experimental or investigational drugs in a clinical study within 24 weeks prior to baseline. Use of a currently marketed drug in a clinical study within 24 weeks prior to baseline would not be exclusionary, provided no other exclusion criteria are met.
  8. Use of immunosuppressive agents, or cytotoxic agents, including cyclophosphamide and azathioprine within 48 weeks prior to baseline.
  9. Previous treatment with fingolimod (GILENYA®, Novartis), dimethyl fumarate (TECFIDERA®, Biogen Idec Inc), glatiramer acetate (COPAXONE®, Teva), interferon-β (either 1a or 1b), intravenous immunoglobulin, or plasmapheresis within 8 weeks prior to baseline.
  10. Use of teriflunomide (AUBAGIO®, Sanofi) within 2 years prior to baseline, except if active washout (with either cholestyramine or activated charcoal) was done 2 months or more prior to baseline.
  11. Prior use of monoclonal antibodies ever, except for: natalizumab (TYSABRI®, Biogen Idec Inc), if given more than 24 weeks prior to baseline AND the patient is John Cunningham (JC) virus antibody test negative (as per medical history)rituximab, ocrelizumab, or ofatumumab, if B cell count (CD19, as per medical history) is higher than 80 cells/μL
  12. Use of mitoxantrone (NOVANTRONE®, Immunex) within 5 years prior to screening. Use of mitoxantrone >5 years before screening is allowed in patients with normal ejection fraction and who did not exceed the total lifetime maximal dose.
  13. Previous use of laquinimod.
  14. Chronic (eg, more than 30 consecutive days or monthly dosing, with the intent of MS disease modification) systemic (intravenous, intramuscular or oral) corticosteroid treatment within 8 weeks prior to baseline.
  15. Previous use of cladribine or alemtuzumab (LEMTRADA®, Sanofi).
  16. Previous total body irradiation or total lymphoid irradiation.
  17. Previous stem cell treatment, cell-based treatment, or bone marrow transplantation of any kind.
  18. Patients who underwent endovascular treatment for chronic cerebrospinal venous insufficiency (CCSVI) within 12 weeks prior to baseline.
  19. Use of moderate/strong inhibitors of cytochrome P450 (CYP) 3A4 within 2 weeks prior to baseline.
  20. Use of inducers of CYP3A4 within 2 weeks prior to baseline.
  21. Pregnancy or breastfeeding.
  22. Serum levels ≥3× upper limit of the normal range (ULN) of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at screening.
  23. Serum direct bilirubin which is ≥2×ULN at screening.
  24. Patients with a clinically significant or unstable medical or surgical condition that (in the opinion of the Investigator) would preclude safe and complete study participation, as determined by medical history, physical examinations, electrocardiogram (ECG), laboratory tests or chest X-ray.
  25. A known history of hypersensitivity to gadolinium (Gd).
  26. Glomerular filtration rate (GFR) < or equal 60 mL/min at screening visit.
  27. Inability to successfully undergo MRI scanning, including claustrophobia.
  28. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to mannitol, meglumine or sodium stearyl fumarate.
CoI: multiple

31 comments:

  1. Hope in MS is always pitched at such a low level. For most diseases, the hope is a cure (no more disease), the hope to halt the disease (not get any worse), or the hope to gain some repair / regain some lost function. The Ocrelizumab trial results are welcome, but we don't yet know which sort of PPMS patients will see benefit or whether any benefit will be sustained over the longer term. Neuroprotective and repair therapies have been discussed for the last 10-15 years, but remain "on the horizon". We need much more effective treatments now - not in 2, 5, 10 years. The slowness of the efforts has killed off much hope for MSers who are in wheelchairs or bedbound. Telling someone that they may be able to get a treatment in two years which may slow down the rate they become disabled by 25%, is hardly a life changing event. I contributed to the Promise 2010 campaign, but have seen no benefit for patients. I contributed to the myelin repair campaign of the UK MS Society, but the breakthrough findings announced four years ago have not even got into the trial stage. My hope remains that someday really effective treatments become available to patients who have to deal with a cruel / unforgiving disease.

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    1. Your comment really struck me, and from the perspective of somebody with MS real progress in terms of treatment is disastrously slow. What can I say, out of Promise 2010 came the phenytoin trial in optic neuritis, which was positive (http://multiple-sclerosis-research.blogspot.com/2015/04/aan-2015-embargo-lifted-early-on-optic.html), and we're still recruiting for PROXIMUS (http://multiple-sclerosis-research.blogspot.com/2014/11/proximus-has-been-given-green-light.html), looking at neuroprotection on top of anti-inflammatory drugs. Both trials will not immediately lead to change of practice, however if we don't want to end up in the corner of quacks treating all over the place with unmitgated risk, we have to follow due procedure and collect the evidence. On the other hand, effective treatment is available for many, and key is to get in early, with increasingly soild evidence this makes a real difference long term. As stated numerous times on this blog we're also committed not to give up on pwMS once they mobilise 'only' in a wheelchair (a cruel cut off for stopping DMT). We'll be back soon with a trial (+ service) design to specifically address the unmet need of disease modification in people with advanced MS (pwAMS).

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  2. So no good news for SPMS patients then?

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  3. Does this not show the problem of off-label prescribing, because if NHS England stops you (presumably it is an issue of price) using this when there is now clear evidence that at least a subset of PPMSers will benefit. If it had a licence this wouldn't be an issue. So does the minister mean it is OK to use off label drugs as long as they are cheap?

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    1. Though I don't expect the minister to make a case in favour of off label prescribing based on price, affordability certainly makes it easier for local decision makers to nod. Off label prescribing is acceptable not only when there is no licensed drug, as the Lucentis vs Avastin has shown. However, given there is currently *no* licensed alternative for pwPPMS but clear evidence in favour of B cell treatment, certainly when disease activity is underpinned by MRI, off label treatment should be considered.

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  4. After reading this blog I can definetley say I am against government run health care even though I was for it before being DXed with MS.

    It's so sad that a drug that is equivalent to Ocrelizumab is readily available on the shelf and approved. Keeping the costs of Pharma down is important, but NICE is not the answer. I will take the US healthcare system over what Europe has even though it has its problems.

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    1. Ocrelizumab, despite the promising trial result hasn't been approved for the treatment of MS yet. Lets hope it will be soon and provided by the NHS. I think you're wrong about the NHS, it isn't perfect by any means but it's certainly better than the alternatives. Health treatment should never be based on the ability to pay.

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    2. "Health treatment should never be based on the ability to pay."

      Absolutely.

      I just wish more big cheeses in pharma would place greater importance on what their new drugs can do to help people, society and humanity, and put less emphasis on lining their pockets.

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    3. The pharma sector appears to be run entirely by accountants, which explains a lot. It needs to change, even the US is waking up to this.

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    4. Before the Affordable Care Act arrived, if you had insurance, and developed a 'costly' illness, you were routinely thrown off your insurance. Good luck getting your treatments then. I know, I live in the U.S. and it happened to one of my best friends. The truth is that there are pros and cons to both systems, but don't live under the illusion that the cons aren't so bad over here. They're just different.

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    5. Actually, the Affordable Care Act is not a single payer system like Britains government run healthcare. It relies on private insurance companies to supply coverage.

      But I agree with you that in the past people could be denied healthcare based on pre-existing conditions. I think the ACA is a good step towards eliminating this behavior as well as attempting to get everyone coverage.

      Is the ACA better than what Britain has? In my view yes. From reading this blog I hear that the attitude in Britain is "wait and see" when someone is diagnosed before they start treatment. In contrast, in the US the mindset is to get people on treatment ASAP. Also it seems monitoring disease activity by MRI is scarce according to comments on this blog where in the US, disease activity is looked at frequently by MRI.

      I have also just now realized why this blog is so biased against Interferons and Glateramer Acetate. It has been decided by NICE that these treatments are not cost effective and cannot be prescribed.

      As somone who is happy with GA and would not like to be forced on an immunosuppressive drug, I would not have this option if I lived in the U.K. because the NICE bureaucrats have decided this for me.

      But why would NICE be re-evaluating their guideance policy on these drugs?

      http://www.nice.org.uk/guidance/indevelopment/gid-tag529

      This does not make any sense to me.

      So I am happy with the ACA as compared to what Britain has and hopefully it can be improved so that everyone has equal care, freedom of choice and quality healthcare for everyone.

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  5. Prof G and his London Bubble! Bah!

    I have PPMS and reside in west Yorkshire. My brother also has PPMS and lives in Maidenhead. He has ben treated with Mitoxantrone and had his house adapted for his needs bu local adult social services.

    I, however, never received any medicine because my neurologist says there is nothing licensed for PPMS. We've also had to pay foe many of our own adaptations because my local authority is underfunded and rubbish.

    The British postcode lottery is alive and kicking, sirs. The affluent southerners get options and attention, the plebeian northerners get nowt. Prof G, using his resources, has a vision for his PPMS suffers whilst my neurologist can't give a fig because he's not operating in the capital of England.

    The NHS is going to be gone within a generation anyhow. We all know it.

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    1. We won't give up without a fight though. And together with our colleagues in Manchester, Leeds, Nottingham, Sheffield,... we're keen trying to stop and improve disease even at an advanced stage. We'll be asking for your feedback into a trial design for people with advanced MS shortly.

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    2. I think you'll find us southerners are in the same boat. I must say your brother is lucky if he gets help, but unlucky to have PPMS. It's all hype, most of our local authority services have been outsourced up north.

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  6. Question:
    Please could someone explain what is meant in Inclusion Criteria No 2 by "...lesions consistent with PPMS in either or both brain and spinal cord". I thought that apart from when a lesion was shown to be active when Gad was used during an MRI, a lesion is a lesion is a lesion. What makes a lesion "consistent with PPMS"? What makes a PPMS lesion different from an RRMS or SPMS lesion on an MRI image?

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    1. Whilst lesions are pathologically very similar in pwRMS and pwPMS, one has to take into account their slightly different 'behaviour' in terms of distribution. The latest version of the McDonald Criteria can be found here: https://en.wikipedia.org/wiki/McDonald_criteria#Revised_Diagnostic_Criteria_.282010.29. You will see that for a diagnosis of PPMS only 1 lesion in a characteristic brain location is required, however this finding must be accompanied by either (i) supportive spinal fluid findings or (ii) at least 2 lesions in the spinal cord. In pwRMS at least one lesion in two characteristic brain locations suffices (evidence of dissemination in space, DIS) as long as there is also evidence of dissemination in time (DIT, various criteria, check the Wikipedia entry). Hope this makes sense...

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    2. Thanks Dr K
      Since my diagnosis a couple of years ago I’ve looked at the McDonald criteria quite a few times as I've tried to understand this crappy disease and what it's done/doing to me. My medical record has me classified as RRMS but I've always thought I was more likely to be PPMS when I look at the various "definitions" provided in multiple sources of info, including the graphs of relapses/disability progression, as what I've experienced fits with the PPMS ones, especially because I've never had what fits with descriptions of relapses. That is, I've never had bouts of severe symptoms, just ongoing deterioration with only a very slightly episodic nature in the early stages around ten years ago when I was nearly 50yo (hindsight is wonderful thing - maybe!) My symptoms also fit with various sources that say that leg parasthesias, balance, bladder and leg function problems tend to be those most likely to be associated with PPMS, and I’ve never had any eyesight symptoms. I have been told that it could have been RRMS early on, just that any relapses were sub-clinical, but my first MRI three years ago showed around 15+ brain lesions and several large spinal ones, so clearly the damage had been happening for some considerable time. There has been virtually no change across several MRIs in the last three years, but my symptoms have continued to get worse. I’ve only had Gad once (used with the most recent MRI), and that showed no visible active lesions, and I’ve never had an LP.

      I know that individual advice is not given on this blog, but and I’m not trying to become an expert, but just gain a greater understanding to help with when I see my neurologist, especially in relation to any possible clinical trials I could participate in in my country, or consideration of any off-label options. Taking IFN-B1-A was a nightmare for me so I stopped it, and it seems pointless to even consider taking any of the newer meds with their greater efficacy in stopping relapses when you don’t have relapses that need to be stopped.

      So, I suppose my key question is how is it decided whether someone has PPMS or SPMS when there is around 8 years between first symptoms (hindsight again) and first consult with a neurologist?

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    3. It's all in the history & documentation! PPMS and SPMS are description of the disease phenotype (relapses > progression= SPMS; no relapses but progression from onset= PPMS). There are characteristics over and above these that separates PP from SP, however only on a group level, for example the larger lesion load in SP vs PPMS, however it's impossible to distinguish solely from looking at an MRI whether somebody has PP or SPMS.

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    4. Thanks again Dr K
      That helps. Both of the neurologists I saw were provided with full documentation of the problems I had experienced going back over several years (lower leg parasthesias, and problems with bladder, leg function and balance - two and a half typed pages of chronological notes about a person who is very healthy and has no other health issues). Both said MS was extremely unlikely because of no clear relapses. With hindsight and knowledge gained since I now know that all of my problems were all MS symptoms.

      MS New Zealand provides a pretty succinct description (and some good graphs)
      "PPMS is characterized by progression of disability from onset, without plateaus or remissions (2a) or with occasional plateaus and temporary minor improvements (2b). A person with PPMS, by definition, does not experience acute attacks. Of people with MS are diagnosed, only 10% have PPMS. In addition, the diagnostic criteria for PPMS are less secure than those for RRMS so that often the diagnosis is only made long after the onset of neurological symptoms and at a time when the person is already living with significant disability."
      http://www.msnz.org.nz/Page.aspx?pid=279
      I can certainly concur with "the person is already living with significant disability" - my EDSS (crappy tool though it is) was 3 at time of being given my diagnosis after my first MRI was eventually done (six months after seeing neuro No 1). When the notes that I provided were taken into account my first MRI was considered so conclusive that an LP was not required.

      So, whether I am now SPMS or have been PPMS since the start, at least I can experience the "relief" noted by some sources that I'm not going to have to worry about suffering devastating acute relapses, and can just get on with adjusting to ongoing deterioration in function. Fortunately my cognition is not yet affected!

      What does seem to me to be important is that with the increase in MS being diagnosed in older age groups, there needs to be some awareness raising about MS being more seriously considered as a possibility in people aged 50+ who are suffering from symptoms which could be MS. This blog has been invaluable for me in learning more, and this blog is pretty consistent in noting that the "group" of symptoms I suffered with for years tend to be more evident in late onset and/or PPMS.

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  7. Is there anyway NICE can accelerate the approval of Ocrelizumab? considering there is no current treatment for PPMS and most will show signs of progression during those 2-3 years.

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    1. The first stop is the EMA. Once it is clear award of a license is likely, Roche will start negotiating with NICE about price. The only option for a very similar treatment at the moment is to identify a neurologist who (i) refers you for an MRI brain, and (ii) if there is evidence of inflammatory activity (Gd+ lesions, or significant increase in lesions compared to a reference scan) makes the case for you to be treated with Rituximab. Alternatively, if you have access to a trial site for Arpeggio - have yourself assessed for eligibility - recruitment will be closing soon!

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  8. What about biotine in high doses? Biotine is cheap and safe.

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  9. "Hope.....hope is a dangerous thing. There's no place for hope on the inside. It will drive a man crazy." Shawshank Redemption 1994 film.

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  10. https://www.youtube.com/watch?v=XDGNsbLayJw

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  11. Hope for the best, prepare for the worst. My grandfather said this. And so did the Dalai Lama (http://www.dalailama.com/news/post/326-dalai-lama-promotes-peace-through-dialogue).

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  12. Given the scant data provided at ECTRIMS about the actual efficacy of Ocrelizumab in the PPMS population as a whole, I would say there is a pretty good chance that any hope being engendered from the current data set is, unfortunately, likely to be false hope.

    Given the results of the Rituxan PPMS trials, it seems readily apparent that the likeliest outcome will be that Ocrelizumab works only on PPMS patients with enhancing lesions, which means it will be effective on about 15% of patients with that diagnosis. The hype that accompanied the pharmaceutical companies announcements regarding Ocrelizumab and PPMS got way ahead of the reality of the data. It's quite telling that the drug company refused to answer any questions regarding patient subgroups when it came to revealing the Ocrelizumab/PPMS data.

    I would think there's actually a pretty good chance that the drug will not get FDA approval for PPMS unless the patient displays enhancing lesions on their MRIs, or has demonstrable relapses.

    Hope is indeed a wonderful thing, but false hope is a killer… I would think it would be contingent upon neurologists treating PPMS patients to clearly explain what the most likely scenarios are regarding Ocrelizumab and the treatment of their disease.

    As a PPMS sufferer myself, I can remember the crushing disappointment of the failed Rituxan PPMS trials. The fact that a retrospective analysis of the data revealed a small subset of patients who were responders is encouraging, but it appears that the Ocrelizumab trial design was overweight with patients fitting the profile of these responders, which, as stated above, represent about one in seven people with PPMS.

    We need to stop looking at immunosuppressants in regards to progressive MS, and develop robust research efforts directed at uncovering the root cause of the smoldering neurodegeneration and then ways of short-circuiting it.

    Climbing off soapbox now (as if I could ever climb onto a soapbox)…

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  13. i suggest you look at the recent presentations of profG and unless he has removed them you can see the data.
    Roche are not going to give you the data in the mad hope that they will get the licence for all of ppms. However it is likely that you are correct that it is active ppmsers that gain the real benefit. The trial was loaded with young/short disease duration and active ppmsers based on the rituximab data. There was an extra 10-15% of active ppmsers above the average 15%.
    They are learning from the past and we should link the data to T2 lesions as not everyone would be active at the time of scan.

    However it shows that PpMSers benefit from anti inflammatories they just need neuroprotectives as well.

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    1. i think inflammation will be at the root of the smouldering you light a match and something burns the embers simmer on cor a long time and neuroprotection without anti inflammatory will not be ideal.
      To test this we would ideally need four groups nothing and then antiinflammation and then neuroprotection and then neuroprotection and anti inflammation. I wonder if we can get this funded as it will be expensive but can we afford not to do it or do we do anti inflammation and anti inflammation + neuroprotection

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