Archive – Page 6 – Prof G's MS Blog Archive

What is HSCT?

I seem to be spending a lot more clinic time explaining to my patients about HSCT. What is happening and why?

HSCT = hematopoietic stem cell transplant

HSCT is simply a rebranding of bone marrow transplantation or BMT. BMT was the term we used when the stem cells had to be harvested by doing a bone marrow aspirates, i.e. a thick needle was inserted into the bone and the marrow sucked out under pressure. This procedure is painful and is done under sedation. I remember it very well when I was a houseman and junior medical registrar, or trainee, I worked on a haem-oncology unit and had to do this procedure. Fortunately, the haematologists have now developed an effective way of mobilising and harvesting stem cells from the blood without having to tap the bone marrow. This is done by giving a small dose of chemotherapy followed by growth factors so that the stem cells spillover from the bone marrow into the blood. These stem cells are harvested and frozen and can then be given after immunoablation therapy. Immunoablation therapy refers to chemotherapy to get rid of your immune cells.

Please note that all that these stem cells do is allow you to receive more potent chemotherapy and work by allowing your bone marrow to recover more quickly. There is nothing magic about this; HSCT in the treatment of MS is simply used to speed up bone marrow recovery, nothing more and nothing less. More rapid bone marrow recovery makes BMT safer.

The stem cells in HSCT don’t go to the brain and spinal cord to repair the damage. This is a common misperception. People think the haemopoietic stem cells are being given to repair the damage that has accrued from having MS. This is why HSCT, like other DMTs, is more effective when used early before MS causes too much damage.

There are different intensities of bone marrow ablation therapy. So-called myeloablative therapy is aimed at wiping out your immune system completely and replacing it with a new immune system. Non-myeloablative therapy is less intense in that it simply depletes your immune system partially and allows it to be rebooted (partially). The non-myeloablative therapy is clearly less risky than the myeloablative therapy but less effective. In other words, more pwMS have a recurrence of their disease activity after non-myeloablative HSCT (NM-HSCT), when compared to ablative-HSCT (A-HSCT). The chemotherapy that is used for NM-HSCT is less toxic. Many in the field believe that if you are going to treat MS with HSCT you need to go the more aggressive route and use the more toxic and risky A-HSCT. They argue that NM-HSCT is not really better than the current high-efficacy drugs we are currently using to manage MS, i.e. alemtuzumab and/or natalizumab and/or ocrelizumab. This is why we are proposing to do a trial comparing alemtuzumab with NM-HSCT to see if NM-HSCT is more efficacious than alemtuzumab and to see if the potential benefits of HSCT warrant the risks.

What are the risks of NM-HSCT? The chances of dying from the NM-HSCT is in the order of 0.3%-1%; i.e. 1-in-330 to a 1-in-100 chance of dying. Then there is the toxicity associated with the chemotherapy; nausea, vomiting, diarrhoea, hair loss, bleeding, infections, infertility and neurotoxicity to name a few. It seems that the more disabled you are the worse the neurotoxicity. If you have lost a lot of nerve fibres already and have reduced brain reserve you handle chemotherapy poorly. The chemotherapy worsens neurological function. This is why a large number of BMT units stopped using this therapy in people with more advanced MS and is the reason why most units have an upper EDSS limit as part of their inclusion criteria.

Once your immune system recovers post-HSCT does not mean it is necessarily back to normal. There is evidence that HSCT may result in a rejuvenation of your immune system and changes the so-called repertoire of your B and T cells. At the moment we don’t know if this is a good or bad thing and what it means for MS. What we do know is that HSCT destroys memory cells from your previous vaccinations. This is why you have to be revaccinated with all your childhood vaccines at ~2 years after HSCT to restore your immune responses to these common infections.

What about secondary autoimmunity? There is data in the literature that pwMS treated with HSCT are at risk of developing secondary autoimmune diseases similar to that which occurs after alemtuzumab treatment. If this is the case I would find it hard to recommend NM-HSCT, over alemtuzumab, unless it was part of a controlled trial, or the person had already failed alemtuzumab.

What about A-HSCT? This now is a different beast compared to NM-HSCT in that the short-term risks associated with the intense chemotherapy needed to ablate the immune system are so much worse. Everything is worse; the diarrhoea tends to be bloody and protracted, mucositis is the norm (the lining of your mouth, throat and intestine slough), infections are more severe, and are potentially life-threatening, there is solid organ toxicity (liver, lungs, kidneys and heart), your bone marrow takes longer to recover and a result you are more likely to need platelet and blood transfusions. A-HSCT is not for the faint-hearted. A large number of HSCT enthusiasts in the autoimmune field are of the opinion A-HSCT is the way to go; the failure rate from NM-HSCT is too high. They argue that if you are going to take the risk, you might as well go for maximum efficacy.

The seemingly miraculous treatment effects with HSCT, for example of people in wheelchairs getting up and walking, is not unique to HSCT. We see these ‘Lazarus effects’ with other highly-effective DMTs. Provided you have sufficient reserve capacity in the brain and spinal cord you will see spontaneous recovery from relapse-related disability once inflammation is switched off and recovery mechanisms are allowed to proceed. Tragically these Lazarus-like examples create unrealistic expectations for pwMS with more advanced disease. Once you have fixed or progressive disability it is likely that you have lost your neurological reserve and hence even if you switch off inflammation with HSCT, or any other anti-inflammatory DMT for that matter, it is unlikely that there will be a significant recovery of function. This is one reason why so many progressive MS trials have failed in the past. Therefore the benefit:risk ratio changes with more advanced disease and its the reason why most HSC units have age and disability cut-offs for pwMS.

Would I refer pwMS for HSCT? Yes, I do. The situation where HSCT is indicated as part of routine clinical care is in the occasional patient with more malignant disease, who have failed licensed treatment options. In these patients, the benefits of HSCT potentially outway the risks of the disease.

In practice, I find the main reason why pwMS say no to HSCT is the infertility risk. The risk of premature ovarian failure, or early menopause, is over 40% and a lot of women when they hear this figure they tend to say no. Similarly, for males, the cyclophosphamide hits the testes hard and if you want to start, or extend, your family you need to bank sperm.

Please remember the human brain is hard-wired to be optimistic. I like to use the gambler’s dilemma as an analogy. No gambler places a bet, or goes into a casino, to lose money; they always believe they are going to be the one that wins the jackpot. No person will sign-up to HSCT believing that they are going to die or develop complications. However, there will always be the unlucky ones who have the serious complications and occasionally die from the procedure, or develops serious delayed adverse complications. If you decide to have HSCT as part of a trial, or as part of routine care, you need to ask yourself the question what if I am the unlucky one? Am I am ready to leave my family and loved ones prematurely? If you answer yes, and yes, then you are ready to take the risks. In the same way, I always tell my patients who sign-up for alemtuzumab treatment that they should expect to develop a secondary autoimmune complication; if they don’t they should count themselves lucky. if they are not prepared to develop a second autoimmune disease then shouldn’t be treated with alemtuzumab.

The following are our local criteria for being referred for HSCT.

ProfG
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Do MSers utilize more healthcare than is necessary?

What can we do to reduce the number of healthcare resources that MSers consume?

This Canadian study shows that pwMS who have fatigue and high physical comorbidity counts (additional neurological problems), anxiety, disruptive pain and perceived functional cognitive difficulties have higher rates of physician encounters, prescriptions filled and hospitalizations. Is this stating the obvious or not?

The more damage MS causes the more problems you will develop and consequently the more healthcare you will need and consume. The solution? Early effective treatment to prevent damage accumulation. This is what we are trying to promote with our ‘Brain Health: Time Matters‘ policy document and what I try and capture in my ‘Holistic Management‘ of MS Tube map. The tube map depicts MS as a journey and as you become more disabled you acquire more symptomatic problems along the way.

For the cynics reading this: please note there is a new line on the map that is still under construction (dotted grey line) with three stops; (1) Long-term remission, (2) MS Cure and (3) Healthy Ageing. This is what I call positive thinking and a message of hope and why our treatment targets in MS need to be more ambitious.

McKay et al. Comorbidities Are Associated with Altered Health Services Use in Multiple Sclerosis: A Prospective Cohort Study. Neuroepidemiology. 2018 May 15;51(1-2):1-10.

BACKGROUND: Persons with multiple sclerosis (MS) use health resources with greater frequency than the general population. However, little is known regarding which patient characteristics might contribute.

OBJECTIVE: The study aimed to evaluate characteristics associated with healthcare use in MS patients.

METHODS: Consecutive MS clinic attendees were recruited (September-November 2010), with clinical, demographic, and patient-completed questionnaires collected at 3 visits over 2 years. Linkage with administrative data (hospital, physician, and pharmacy records) provided healthcare use outcomes until December 31, 2013. Findings were reported as adjusted rate ratios (adjRRs) using negative binomial regression.

RESULTS: A total of 340 MS patients with a mean (SD) age of 48.4 (12.0) years and subsequent follow-up of 3.1 (0.34) years were included. Fatigue and high physical comorbidity count (≥3 vs. none) were significantly associated with higher rates of physician encounters (adjRRs: 1.37 and 1.52, respectively), prescriptions filled (adjRRs: 1.25 and 1.40), and hospitalizations (adjRRs: 4.02 and 3.45). In addition, anxiety, disruptive pain, and perceived functional cognitive difficulties were associated with higher rates of physician encounters and prescriptions dispensed (adjRR ranged from 1.28 to 1.48).

DISCUSSION: The presence of fatigue and higher physical comorbidity burden were associated with higher rates of health services use. Findings have implications for those examining healthcare burden or organizing health services for persons with MS.

ProfG
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Have your say on the big NHS England MS debate?

You may be aware that NHS England has just closed the public consultation period for the new NHS England Treatment MS DMT Algorithm. The aim of the algorithm is part of a troika, along with Blueteq and MDTs (multidisciplinary team meetings) to reduce the variation in prescribing of DMTs across England. The question is will this algorithm achieve its aim?

The following is the debate we had on this topic last week at the ABN in Birmingham. Please have your say; watch the debate and vote.

ProfG
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2018 List of Best MS Blogs

We have made the Healthline 2018 list of “Best MS Blogs“. We have changed the blog in the last 6 months; fewer posts, more guests and less science. Do you think this has improved the blog? We would welcome suggestions going forward. For example, we are thinking of migrating the blog from Blogger onto a better and more responsive platform.

ProfG
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Care Home vs. Independence

A commentator brought this BBC interview to our attention as an example of what is happening to people with MS living in England. I would be interested to know if there are any other examples of this happening across the country. We need to do something about it. Can anyone help?

ProfG
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News: children with MS get their first licensed DMT

It may be old news, but it is very good news; the FDA has just licensed fingolimod as the first DMT for paediatric MS.

I am sure parents of children with MS living in the US are relieved that they finally have a licensed therapy for their children. I sincerely hope the EMA now steps up to the mark and does the same in Europe.

As a reminder, the following are the headline results from the study that were presented at ECTRIMS last year. It is clear that fingolimod is far superior to interferon-beta in this younger population.

ProfG
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Not managing expectations in someone with PPMS

Not managing expectations results in angry patients. How not to get it right?

Please note that the details of this case has been fictionalised, but illustrate a real-life scenario.

Yesterday one of my new patients with primary progressive MS came back for a follow-up visit after undergoing investigations to assess whether, or not, he was eligible for our compassionate use programme of off-label cladribine. He had been specifically referred to me by his consultant neurologist for cladribine therapy. He had rapidly progressive MS and gone from diagnosis to EDSS 6.5 (bilateral support) in approximately 8 years, with an 18-month history of a prodrome, i.e. he had noticed mild foot drop on exercise and this had been dismissed by his GP as a possible trapped nerve. Please note that 18 months from symptom onset to diagnosis of PPMS is actually quite quick.

MS had already taken its toll, he was single having split-up with his long-term partner and had already had to give up work because of MS. He had sexual dysfunction, bladder and bowel symptoms, fatigue and spasticity. The spasticity was causing nighttime leg jerks, or spasms, that were waking him up in the early hours of the morning. As a result, he had interrupted sleep and never woke feeling refreshed. He managed his own activities of daily living but was very slow at doing manual tasks. He was unable to do domestic chores but was still able to drive. He was using a light-weight electric scooter for outdoor mobility. The scooter had been purchased for him by his family. As a result of leg weakness and a dropped foot on the right, he had had several falls. He had previously had physiotherapy for his walking difficulties and had been prescribed a foot-up device, which he was not using, and a lightweight walker. Other issues were social isolation, he rarely got out to meet family and friends, he had a poor diet, a current smoking history of 15-20 roll-up cigarettes per day and he did no exercise. He was also depressed and very anxious about the future.

After assessing him I ordered an MRI of his brain and spinal cord with gadolinium enhancement as well as a lumbar puncture to measure his spinal fluid neurofilament light chain (NFL) levels. His MRI showed a moderate brain lesion load, several spinal cord lesions with cord atrophy. None of the lesions enhanced after the administration of contrast or gadolinium. His spinal fluid showed locally synthesised oligoclonal IgG bands, compatible with his diagnosis of PPMS, and the NFL levels were well within the normal range for his age.

In summary, we have a middle-aged man with rapidly worsening PPMS with no signs of active focal inflammation on MRI or on spinal fluid analysis (NFL levels), i.e. his PPMS was inactive. I told him that based on our current treatment guidelines he would not be eligible for treatment with off-label cladribine. He was furious and wanted to know why. I tried to explain to him that we have no hard evidence at present on whether or not cladribine is effective in people with inactive PPMS. I said to him that his worsening disability may be due to damage from the past and/or early ageing in neuronal pathways in the spinal cord with no reserve capacity. He didn’t buy this explanation and wanted cladribine regardless of the potential consequences to his health. I was not prepared to give in and tried to give him hope. He may become eligible for ocrelizumab if NICE gives it a green light for use on the NHS in PPMS. However, the NICE single technology appraisal of ocrelizumab for the treatment of PPMS is unlikely to happen for many months, possibly years. He isn’t prepared to wait. Another option I offered him was the possibility of volunteering for an upcoming treatment trial. I explained that both alemtuzumab (EDSS <=6.5) and ocrelizumab (EDSS <=8.0) PPMS trials will be recruiting patients later on this year. He asked if they were placebo-controlled and I said yes. He was adamant that he is not prepared to go into a placebo-controlled trial. The consultation ended with him telling me that he will have to make plans to travel abroad for HSCT. I explained to him why I thought the latter was not a good idea, but he was not in the right frame of mind to accept any further advice from me. In short, I had let him down.

On leaving my consulting room he accused me of not caring and that I should have given him treatment despite having no evidence. Therein lies the rub; people with PPMS are so desperate to try anything to halt, or slow down, their worsening disability that they are prepared to take risks without necessarily the evidence of any potential benefit. We the healthcare professionals are trying our best to practice evidence-based medicine and where we don’t have evidence to at least apply some basic scientific principles. In an ideal world, I would be treating this patient with ocrelizumab and in a less than ideal world with off-label rituximab. Unfortunately, the NHS does not cover the costs of rituximab for PPMS. Cladribine may become an option in the future when we have data that could support some efficacy in worsening, but inactive, PPMS. This is why it is so important that DrK’s proposed Chariot-MS study is funded. As for HSCT, I am not aware of any evidence to support its use in worsening, inactive, PPMS. In fact with an EDSS of 6.5, I suspect the myeloablative chemotherapy, which is potentially neurotoxic, may actually make things worse. This why our London HSCT treatment criteria exclude patients who have more advanced MS.

We seem to be caught between a rock and a hard place. We are trying to give PPMSers hope, but are we selling them false hope? In future, I am going to spell out more clearly how we define active PPMS so that when patients come for follow-up assessments they are forewarned and prepared for a possible decision of no treatment. Would you agree?

MSers also need to be made aware of therapeutic lag and reserve capacity. What does this mean for this patient? Even if we could initiate ocrelizumab next week we may not be able to prevent further deterioration in his lower limb function, i.e. progression today is driven by inflammatory damage in the past and by switching off inflammation now this may not be noticeable to him. In other words, progressive MSers may not be able to notice a slowing down in worsening of their progression. To expect flat-lining and improvement in functioning we probably need add-on neuroprotective and remyelination therapies and possibly even neurorestorative therapies. Please note add-on therapies targeting recovery of function will only work long-term if they are given on top of anti-inflammatory DMTs. What is the point of repairing and protecting the damaged nervous system to leave MS untreated?

Do you agree all MSers with advanced MS and worsening disability should be informed of this information?

Another component that needs to be tackled is this man’s lifestyle. He is smoking that is almost certainly making him progress faster. In addition, there is a lot of symptomatic therapies that could be tried to help him. He needs an anti-spastic agent and possible treatments for his bladder, bowel and sexual function. He may also be eligible for a trial of fampridine. A graded exercise programme may help with his mood and improve his long-term outcome. It is important to remember that treating MS, in particular, advanced MS, is a partnership between the patient and the team of HCPs looking after them. This patient was expecting a quick and easy pharmacological solution to his advanced MS and was not addressing lifestyle issues that are just as important as any DMT.

ProfG
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A trial of a possible remyelinating drug in multiple sclerosis

Do you live in the UK? You may want to consider volunteering to participate in a very exciting remyelination trial.

Nerves within the brain and spinal cord are normally protected by a surrounding layer of a substance called myelin. In multiple sclerosis, the immune system of the body attacks this myelin, stripping it off the nerve fibres. This causes the nerves to malfunction, leading to your multiple sclerosis symptoms. Animal studies have shown that a group of drugs can stimulate cells in the brain to repair damaged myelin. This process is called “remyelination”. One of the drugs in this group is bexarotene, a capsule already used as an anti-cancer medication. We believe that bexarotene may also promote remyelination in people with multiple sclerosis, which could potentially reverse or alleviate symptoms. The purpose of this research is to assess whether bexarotene causes side effects in people with multiple sclerosis who are also taking disease-modifying drugs and also to assess whether it really can promote remyelination.

Participants in the trial take several capsules (which might be bexarotene or a placebo) a day for 6 months and remyelination is assessed by one MRI scan at the beginning of this six-month period and one at the end.

The trial centres are at Cambridge and Edinburgh.

Participants need to live reasonably close to these centres as frequent visiting (at times weekly) is required.

Participants should have relapsing-remitting multiple sclerosis, need to be able to walk, and should be taking a first-line disease-modifying drug (especially Tecfidera, etc.).

If you wish to be considered for the trial, please ask your GP or consultant to refer you to:

Prof Alasdair Coles
Department of Clinical Neurosciences,
Clifford Albutt Building, Level 4,
Cambridge Biomedical Campus,
Cambridge CB2 0AH

OR:

Dr Peter Connick
The Anne Rowling Regenerative Neurology Clinic
University of Edinburgh
Chancellor’s Building
49 Little France Crescent
Edinburgh EH16 4SB

Are you attending the ABN?

Are you attending the ABN next week? If, yes you may be interested in hearing a debate.

If you are free on Wednesday evening, the 9th May, and are attending the ABN in Birmingham please join the Neurology Academy to hear a debate on whether or not NHS England’s proposed Treatment Algorithm for disease-modifying therapies in multiple sclerosis will achieve their aim of reducing the wide variation in DMT prescribing across England.

The Neurology Academy is an innovative education provider for clinicians, specialist nurses and professions allied to medicine. The training programs focus on both disease management and service transformation. Each priority condition is led by an Academic Faculty of practising clinicians who operate within a separate disease focussed Academy, for example, the MS Academy.

MS Academy ABN 2018 – Venue Hall 7

19:00: Assemble for drink, buffet and networking

19:30: Debate – The proposed new NHS England MS Prescribing Guidelines will stop the current wide variation in DMT prescribing across England (YES – David Paling / NO – Gavin Giovannoni).
20:15: Presentation about the Academy
20:30: Questions and depart

Please RSVP via this link.

Thank you.

Gavin Giovannoni & David Paling
Director & Strategic Director MS Academy

#MSis1not2or3diseases: do you agree?

This post makes the case, yet again, for MS being one disease and that PPMS is no different to other types of MS. Do you agree?

I have had the busiest week clinically for some time with four MS clinics in fours days. I typically only do 1.25 clinics per week (one every Tuesday and one on the first Thursday of the month). Why so little? I am only employed by the NHS for 20% of my time with 80% earmarked for research, teaching, management and other academic activities (grant and paper writing, manuscript and grant reviews, clinical trials, work for charities, Brain Health and MS in the 21st Century initiatives, blogging and social media activities, consulting, etc.).

The week was tough as I have had to deal with severe jet-lag from the AAN, but overall it was very enjoyable.

Several patients I saw had self-diagnosed themselves as having secondary progressive MS and asked me if I agreed with them. In comparison, several patients with more advanced MS, who were clearly getting worse, were in denial about the possibility of having entered the so-called progressive phase of the disease.

The issue I have is that since we published our therapeutic lag and asynchronous progressive MS hypotheses, under the length-dependent axonopathy theory of MS I am having increasing difficulty sticking to the old terminology that splits MS into two or three diseases. I think as a community the time is right to change the way the world thinks about the classification of MS. It is time to energise our campaign around #MSis1not2or3diseases. Do you agree?

People in the field of MS simply accept the dogma that PPMS in non-inflammatory form of MS and that PPMSers don’t have relapses and that PPMS is a different disease to relapse-onset MS.

Studies looking at the pathology of progressive MS show without doubt that PPMS is inflammatory, albeit at a slightly lower level than SPMS. Because we view MS through the spectacles of an MRI scanner people think PPMS is non-inflammatory; PPMSers have fewer new or gadolinium-enhancing lesions. This is wrong, PPMSers have both. In addition, focal inflammation may be occurring at a level below the detection level of the MRI. What an MRI sees in relation to focal lesions is simply the tip of the iceberg. This is why we are increasingly using spinal fluid neurofilament levels to monitor disease activity.

Please note almost all PPMSers have oligoclonal IgG in their CSF. If there were no inflammation surely you would expect PPMS to be OCBs negative. In addition in almost all PPMS trials done to date a proportion, albeit a small proportion, go onto have relapses. In the Rituximab PPMS trial (Olympus), 11 out of 439 (2.5%) of study subjects had a relapse during the 96 weeks of the trial. In the more recent Ocrelizumab (ORATORIO) study protocol-defined relapses were reported for 11% of subjects in the placebo group and 5% subjects in the ocrelizumab group. Similarly, about 5% of study subjects in the glatiramer acetate PPMS (PROMISE) trial had relapses. Unfortunately, the exact number of relapses is not reported in the main manuscript. What is reported is MRI activity; 14% of 938 study subjects had Gd-enhancing lesions on MRI during the study. The latter is the MRI equivalent of relapses.

In summary, PPMSers have relapses. Based on this data how can we say that PPMS is non-relapsing?

Some people still claim that PPMS is a different disease to SPMS. It not uncommon in siblings pairs with MS for one to have relapse-onset MS and the other to have PPMS. The figure from a UK sibling study is ~25%. This fact alone indicates to me that relapse onset and PPMS are the same disease. Other arguments in favour of PPMS and SPMS being the same disease relates to genetic and natural history studies. PPMSers and relapse-onset MSers have the same genetic background. Once people with relapse-onset MS enter the so-called clinical phase of SPMS they progress at exactly the same rate as PPMSers.

It is for these reasons that I am convinced MS is one disease and that there is a strong case for doing trials on combined populations of so-called advanced MS. In other words, we should combine PPMS and SPMS populations into one study. I am aware that this is a controversial topic, particularly in the eyes of the regulators, but it needs serious consideration. If we don’t do this then treatments will continue to be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. This is not in the interests of pwMS. Additional trials cost money and time. Time is not a something that progressive MSers have on their side. Five years in the life of someone with advanced MS may be the difference between using a walking-stick and becoming bed-bound.

Another issue is the concept that still pervades the field is that once you have progressive MS it is untreatable. One patient said to me: ‘but, SPMS is an untreatable disease’. These attitudes entrench the concept of the therapeutic window in MS and perpetuate the concept that it is futile to treat SPMS. I disagree with both of these positions and prepared to go out on a limb and state 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. Both the ASCEND (natalizumab) and EXPAND (siponimod) Trials were clearly positive in SPMS. Although the natalizumab (ASCEND) study did not hit the desired primary outcome natalizumab did show a strong treatment effect on hand and arm function. Surely a treatment that protects upper limb function in people with SPMS is worth the effort? These observations underpin our #ThinkHand campaign and why we want to do our #ChariotMS study. To quote one of my patients with SPMS: ‘Now that I am in a wheelchair my hands and arms have become my legs’.

Do I also need to remind you that the ORATORIO trial of ocrelizumab in PPMS was also positive? Is ocrelizumab really superior to natalizumab? I would argue no. 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 done on subjects with a disability level of EDSS of 6.0 (unilateral support) or 6.5 (bilateral support) that 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 4-5 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 predicted correctly that if the ASCEND trial had been longer in duration then it would 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, which is why I keep badgering Biogen to do an ASCEND-plus trial; i.e. to redo the ASCEND trial and include MSers in wheelchairs and to design the study with the 9-HPT being the primary outcome measure. This is what we are doing with ocrelizumab in PPMS; Roche will hopefully be in a position to announce the ORATORIO-plus trial based on these exact principles. I am convinced these hypotheses are correct as the treatment effect of ocrelizumab was greater on upper limb function, as assessed using the 9-hole peg test, than on lower limb function (EDSS & T25FW) in the ORATORIO PPMS study.

So what have we learnt?

That non-relapsing progressive MS 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.

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.

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 population.

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 has become a reality (watch this space).

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 ocrelizumab, natalizumab and siponimod have produced positive trial results in these populations; please note my emphasis on positive. Because of this, we have been lobbying Pharma to do trials in advanced progressive MS (both PPMS and SPMS combined) with the highly effective DMTs, i.e. natalizumab, alemtuzumab, ocrelizumab, ofatumumab, cladribine and ozanimod. The good news is that alemtuzumab is going into PPMS (sadly only up to EDSS 6.5), ocrelizumab back into PPMS (up to EDSS 8.0) and possibly cladribine (up to EDSS 8.0, #ChariotMS). We wait to hear about whether or not ofatumumab, ozanimod and natalizumab will be going into progressive MS and what cutoffs of EDSS will be used.

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 unemployed 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 say early MS when preservation of physical functioning and employment 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, i.e. for MSers in wheelchairs. 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 counterintuitive but it makes a lot of sense; 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.

I can see a world where the same DMT is more expensive when used in early MS and as the patient becomes more disabled the price of the drug drops. 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 not cost-effective at their stage of the disease?

ProfG
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