Tag: primary progressive

Participating in Oratorio-Hand?

At the recent ORATORIO-HAND investigators’ meetings in Barcelona and Athens, several investigators’ made the point that it may be hard to retain people with PPMS in this trial because ocrelizumab has already been licensed to treat MS. I said YES and NO. 

For one a lot of neurologists, HCPs and payers don’t think the original ORATORIO trial was positive. They think the trial was driven by the 25% or so of the subjects with PPMS who had active disease, i.e. those with Gad-enhancing lesions at baseline. I have even heard some people claim that this trial was positive because it was contaminated by relapsing patients. This was not the case, all subjects had to have PPMS to get into this study. Any history of previous relapse excluded them from the trial. As a result of this doubt, many countries and insurance companies have not agreed to license or reimburse ocrelizumab for PPMS. To convince the naysayers, laggards and sceptics we need another PPMS trial to confirm the original results and extend the findings into pwPPSM with more advanced disease to show that ocrelizumab has a treatment effect in older and more disabled pwPPMS. This is why our age cutoff for the ORATORIO-HAND study is 65 and EDSS cut-off is 8.0 (wheelchair users). In the original ORATORIO study, these cutoffs were 55 years and EDSS of 6.5 (bilateral support, but still mobile). 

Statisticians will tell you that when you only do one trial, which is positive, there is about a 1 in 20 to 40 (2.5% to 5%) chance that result could be positive by chance. In statistical jargon, this is referred to as a false-positive result or type 1 error. This is why the regulators usually require two positive trials to license a product; the first trial to test the hypothesis and the second to confirm the results of the first trial. If one trial is positive and the second trial is negative, or vice versa, this usually results in a third trial being required. This is what happened with laquinimod in RRMS; you may recall the third trial (CONCERTO) turning out to be negative so the laquinimod MS development programme was halted. Herein lies a hidden danger. If ORATORIO-HAND is negative and does not confirm a significant treatment effect in PPMS it could be used by regulatory authorities to question the result of the ORATORIO trial and potentially withdraw the license. A negative result will justify payers refusal to reimburse the costs of ocrelizumab to treat PPMS. I am confident this is not going to happen, but we need your help to makes sure this does not happen. 

The ORATORIO-HAND is a very well-designed study and is adequately powered to give a positive result. The scientific principles underpinning this study are sound. However, if too many subjects drop-out to accept being treated with ocrelizumab when it is reimbursed in their countries or game the trial, i.e. find a way to unbind themselves, and drop-out this could potentially result in the study being underpowered, i.e. there are too few subjects to show a significant result when comparing placebo and active treatment groups. If this happens it could not only jeopardise treatment for themselves but the whole PPMS community. This is why I am appealing to all potential ORATORIO-HAND trial subjects if you are not sure about your longterm commitment to the trial you should not volunteer. 

We are very aware that half the trial subjects will be allocated to placebo. Someone investigators asked why didn’t we make the randomisation 2:1, i.e. for every one person on placebo two people would be allocated ocrelizumab. The logic is that by having a 2-out-of-3 chance of being on active treatment the more likely pwPPMS are likely to volunteer for the study and to stay the distance. There are two reasons for the one-to-one randomisation ratio; time and possibly cost. Increasing the time it takes to recruit study participants is important. We estimate to recruit another 500 subjects, to allow a 2:1 ratio, would take another 12-15 months, which means we would be exposing a third of the subjects to placebo for an additional 12-15 months and potentially denying many pwPPMS across the world earlier access to the ocrelizumab. A 12-15 month extension to the recruitment phase means 12-15 month delay for drug getting to wider PPMS population. These are the factors that convinced the steering committee to choose the 1:1 randomisation ratio. Although cost is an obvious potential consideration we didn’t even ask senior management at Roche the question. 

At the end of the day, we are asking pwPPMS to be altruistic. We are asking you to volunteer for a study and have a 50% chance of being randomised to a placebo knowing that ocrelizumab may be available to you as part of routine clinical practice or could become available to you during the trial. I know some people will ask does it have to be a randomised double-blind controlled trial? Could we generate the evidence in another way? The answer is no; the regulators will only change the label of ocrelizumab if the study is done to their standards. As you are aware it is virtually impossible to get a healthcare system-wide adoption of an MS treatment without a marketing authorisation from the appropriate regulatory body. 

There are also other advantages to being in a trial. We don’t know why but trial participants tend to do better than non-trial participants even if you are randomised to placebo. This may relate to better care offered in a trial or participating in a trial has psychological benefits that can’t be quantified. I favour the latter explanation. There is evidence that people who have a purpose, a sense of belonging and are valued have better health outcomes than people without. Being a trial participant gives you a sense of purpose and being valued in that they are contributing the greater good. I have also noticed over the years that trial participation expands social capital; trial participants get to know the trial staff and other trial participants. I even know of two study subjects from one of the early trials who ended up marrying each other. Others have become friends and see each other outside the trial unit; I have bumped into two of trials participants in a local east curry house together.  These intangibles can’t be quantified, but they definitely exist. 

In countries in which ocrelizumab is not licensed or reimbursed for treating PPMS the advantages of participating in the ORATORIO-HAND study are obvious. But even in countries where ocrelizumab is reimbursed receiving it as part of a trial may help as well. Although we can’t pay for you to participate in the trial all of your out-of-pocket expenses related to travel will be covered. 

I want to emphasise the positive of ORATORIO-HAND. For decades pwPPMS have felt neglected, ignored and left to smoulder away. Not anymore. The fact that the first ORATORIO trial was positive has shifted the goalposts and there will now be a flurry of PPMS trials. If ORATORIO-HAND fully recruits and is completed without too many dropouts the study will change the playing field for good. It will mean that PPMS is truly modifiable regardless of disease activity and potentially even people in wheelchairs will benefit. Getting a license for ocrelizumab in wheelchair users will affect the DMT stopping criteria, in other words even if you have to start using a wheelchair the treatment will have to be continued to preserve your arm and hand function. More importantly, it will get the whole MS community to say ‘Yes, we now agree that ocrelizumab works in PPMS’ and will allow pwPPMS across the world to access treatment. 

We acknowledge that there are many legitimate reasons for why study subjects dropouts in clinical trials. We have factored this into the power calculations. What I am focusing on here is excess drop-outs over and above what we expect to occur from experience of other ocrelizumab trials. 

This post is simply rehearsing some of the reasons for pwPPMS who volunteer for the ORATORIO-HAND study to stay the distance and complete the study. Please let me know if you agree, or disagree, with these points. I am also keen to find other reasons to help the many participating centres retain their patients in this trial. 

CoI: multiple; importantly, I am the principal investigator on the ORATORIO-HAND study and I want to give this trial the maximum chance of being successful. Our #ThinkHand campaign will only be judged a success if and when we get a DMT licensed to protect upper limb and hand function in pwMS. 

O’HAND

I am very excited and proud to be attending and speaking at the first European Oratoria-HAND, or O’Hand, study investigator meeting in Barcelona. With Chariot-MS, the O’HAND study is the culmination of more than 4 years of work and campaigning for Barts-MS. 

However, our #ThinkHand campaign will only be considered a true success if we get a positive outcome from one of our studies and a DMT gets licensed to protect, or delay loss of, hand and arm function in people with more advanced MS. These trials have the potential to change the field and make more advanced MS modifiable. Many cynics think we are wasting our time. But if you have MS and you lose your lower limb function you become dependent on your hand and arms to maintain your independence. In other words, your arms become your legs. 

The following is my presentation from the meeting, which you can download from my bespoke SlideShare site. 

O’HAND Eligibility Criteria

Ages Eligible for Study:  18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:  All
Accepts Healthy Volunteers:  No

Inclusion Criteria:

  • EDSS score at screening and baseline >= 3.0 to 8.0, inclusive
  • Disease duration from the onset of MS symptoms:

Less than 15 years in patients with an EDSS at screening > 5.0 Less than 10 years in patients with an EDSS at screening <= 5.0

  • Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen: Elevated IgG index or one or more IgG oligoclonal bands detected by isoelectric focusing
  • Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands)
  • Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline
  • Patients previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
  • For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

Exclusion Criteria:

  • History of relapsing-remitting or secondary progressive MS at screening
  • Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease
  • Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML)
  • Known active malignancy or are being actively monitored for recurrence of malignancy
  • Immunocompromised state
  • Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
  • Inability to complete an MRI or contraindication to Gd administration.
  • Patients requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization.
  • Contraindications to mandatory premedications for infusion-related reactions, including:

uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines

  • Known presence of other neurologic disorders
  • Pregnant or breastfeeding, or intending to become pregnant during the study and 6 months after last infusion of the study drug
  • Lack of peripheral venous access
  • Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
  • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
  • History of alcohol or other drug abuse
  • History of primary or secondary immunodeficiency
  • Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS
  • Previous treatment with B-cell targeting therapies
  • Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
  • Any previous history of transplantation or anti-rejection therapy
  • Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
  • Systemic corticosteroid therapy within 4 weeks prior to screening
  • Positive serum hCG measured at screening or positive urine β-hCG at baseline
  • Positive screening tests for hepatitis B
  • Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above
  • Lack of MRI activity at screening/baseline if more than 650 patients without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 patients with MRI activity will be randomized

Eligibility Criteria for Open-Label Extension Phase:

  • Completed the double-blind treatment phase of the trial or have received PDP OCR in the FU1 phase, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Patients who withdrew from study treatment and received another disease-modifying therapy (DMT) or commercial ocrelizumab will not be allowed to enter in the OLE phase.
  • Meet the re-treatment criteria for ocrelizumab
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
  • For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

CoI: I am the principal investigator on the O’Hand study

What is MS?

The more I read,  think and assimilate information the more I realise that the real pathology behind MS is not the new acute lesion or relapse, but what is going on behind the scenes in the so-called slowly expanding chronic MS lesion or SEL. 

MS is a smouldering disease. 

In an analysis of the ocrelizumab-PPMS or ORATORIO trial, it is clear that SELs already existed in the brains of PPMSers when they started the trial and best predicted their clinical course during the trial. In contrast, brain atrophy or brain volume loss and new lesion activity did not predict disability progression. What is nice about this analysis is that it is in a PPMS population with a very low relapse rate, which excludes relapses as a confounder. 

I am not that concerned about brain volume loss not predicting outcome in this population, because it is out of sync with clinical outcomes; i.e. brain volume loss today is caused by pathology 2-3 years ago and hence needs to be correlated with clinical outcomes in the past. 

What is important in this study is that new MRI activity in the form of new T2 lesions did not predict disability worsening. In other words, focal inflammation is not associated with clinical outcome. In comparison, SELs or smouldering MS predicted clinical outcome. Based on basic medical philosophical principles around the definition of surrogate markers it is clear that new T2 lesions can’t be the disease we call MS, but SELs can. 

It is clear to me that MS is a biological disease and not an MRIscopic disease, i.e. what you see on MRI is the tip, of the tip, of the iceberg and that most of MS pathology is hidden from view when using conventional MRI. This is why you still deteriorate despite being NEDA (with no evident new disease activity). The NEDA in this context is referring to the absence of focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind the worsening despite being NEDA is driven by the delayed neuroaxonal loss from previous damage, ongoing diffuse inflammation which has become independent of focal lesions (innate activation), ageing mechanisms or focal inflammatory lesions that are too small to be detected with our monitoring tools. Of all the processes listed here, the last one is the only one that is realistically modifiable by our current DMTs. 

The really important question this analysis raises is that when you treat someone with a DMT and they become NEDA how do you know they don’t have ongoing smouldering MS and hence would benefit from being escalated to a more effective DMT or should be included in add-on combination therapy trial? This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. Only then will we be able to start answering important questions. For example, does changing treatment in people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab result in them doing better? The ORATORIO analysis below would suggest the treatment effect in this situation is small. This is why we are going to need a new generation of add-on treatments that target CNS pathology, for example, hot microglia, antivirals (EBV and HERVs), CNS-penetrant anti-B-cell and plasma cell agents, neuroprotectives, etc. 

I have made the point that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease.  I don’t buy this because a proportion of pwMS who have been treated early on with an immune reconstitution therapy or IRT, in particular, alemtuzumab or HSCT, appear to be in very longterm remission and may even be cured of their MS (see the previous post on this topic). Some would argue, I included, that this group of patients has not been followed up for long enough to be sure they have been cured. I agree and this is why we need a deep phenotyping study to assess whether or not these patients have any evidence of ongoing MS disease activity. This study would help define smouldering MS, by looking for its absence. 

The MRI-centric view of MS has lulled many of us into a false sense of security and has resulted in us classifying MS as a focal inflammatory autoimmune disease of the CNS. In reality, MS is a diffuse disease of the CNS and the focal inflammatory events are simply the immune response to what causes MS. This is why the field hypothesis of MS is so relevant and fundamentally challenges our worldview of MS. 

If we don’t change our worldview of MS and explore what is happening in the trenches alongside the one we currently have our heads buried in we will be letting down the next generation of MSers. 

Image from ‘when is a paradigm shift required‘.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. BRAIN 2019: 142; 2787–2799. 

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/ evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1- weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

CoI: multiple

OXO Study

We want to build a sandwich to tackle the many facets of multiple sclerosis that result in neuroaxonal loss. At the base of treatment pyramid, we need an anti-inflammatory onto which we want to add a neuroprotectant, i.e. the combination therapy strategy.

You need to protect damaged and vulnerable axons so that you can then remyelinate them or restore their function. We assume this makes sense, but still, we get push back from many in the field who are determined to still do monotherapy neuroprotective trials. 

What is the point of protecting an axon, allowing it to be remyelinated and to recover function for it to be damaged again in the next round of inflammatory attack? 

Barts-MS Dictum: It makes no biological sense to do monotherapy MS neuroprotective trials in the modern era.

With this in mind, we had a ‘brainstorming’ session last week and came up with a new neuroprotective trial design in primary progressive MS; it is called the OXO PPMS trial or  ‘Add-on OXcarbazepine to Ocrelizumab in PPMS Study’. 

Why PPMS? We feel that PPMS has a massive unmet need and that as ocrelizumab is now licensed as the only DMT in PPMS it makes an ideal platform therapy. We have chosen oxcarbazepine, a sodium channel blocker, as our add-on agent because we have pilot data (animal and clinical) showing it may work and it seems to be better tolerated than other sodium channel blockers. In an ideal world, we would want this study to be done with a new agent that has a long patent life, which would allow Pharma to invest in the necessary studies to get the drug licensed. But alas we can’t find a Pharma company with a new sodium channel blockers who would be interested in MS.

Raj Kapoor, David Baker and I have spent an extraordinary amount of time trying to get Big Pharma to buy into the add-on sodium channel blocker neuroprotection paradigm. Sadly none of the decision-makers has bought into the paradigm, yet. Just maybe with new data and the fact that all the low-hanging fruit on the MS tree has been picked they may change their minds. 

Please note that neuroprotection is only a small part of the solution to worsening or progressive MS. To tackle this problem we need a lot more than neuroprotection, which is why we need to manage MS holistically. 

To reiterate the philosophy of marginal gains “if you break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together. This also means avoiding things that make MS worse”. This is why anti-ageing strategies, in particular, lifestyle factors, need to be included in the longterm treatment strategy to manage MS.  

What do you think of the OXO PPMS study? If you have PPMS would you volunteer for this study? 

CoI: multiple

25 years

I mentioned in a comment yesterday that “MS is unrecognisable to what it was 25 years ago. It is all about early diagnosis and early effective treatment; if you miss out on these it is not good news”. In response, a commentator said “what it really was 25 years ago … and what you remember are going to be different” and “if someone has PPMS …. it’s not”. 

This commentator is wrong on both accounts.

When I started my training as an MSologist working for W. Ian McDonald at Queen Square I recall us having to see MSers with very severe and disabling relapses on a weekly basis. We always had one or two MSers on the wards; admitted to hospital to manage severe relapses, pressure sores, fractures and severe contractures. This rarely happens now. The only patients with relapses that get admitted tend to be patients coming via A&E with their first attack, i.e. their initial presentation. DMTs don’t only reduce relapses they reduce the severity of attacks. I estimate that the use of high-dose steroids to treat relapses has dropped off by over 80%. Most of our RRMSers are being treated to target and are NEDA and relatively stable. We know that prognosis for relapse-onset MS has changed. With DMTs, in particular, high-efficacy DMTs, we have revolutionised the outcome for people with the disease; fewer relapses, milder relapses, less disability, fewer people with SPMS, improved survival, better symptomatic treatments, etc. 

What about PPMS? Firstly, the proportion of people being diagnosed with PPMS has fallen from about 15% of the new, or incident, cases to 5%. Why? This is because neurologists don’t label people as having PPMS so that they can offer them treatment. Even those with a diagnosis of PPMS are being treated in most countries, with either licensed DMTs or off-label treatments such as rituximab. At Barts-MS we have a cohort of our PPMSers on rituximab and an increasing number with active PPMS on off-label cladribine. I also have quite a large number of PPMSers who I still follow who I treated with mitoxantrone. We are also offering an increasing number of PPMSers HSCT. In fact, I saw one of my patients with PPMS, who had HSCT in February this year, in clinic last week. She seems to have done well; i.e. she is stable and says her fatigue levels are much better. And finally, we have ocrelizumab licensed and available to treat early, active, PPMS. Ocrelizumab delays the need for a wheelchair by about 5 years and maintains arm and hand function by about 9 years. Is this not an improvement on what was available 25 years ago? In addition, there is a lot of activity in terms of PPMS trials. We are about to start ORATORIO-HAND, the second ocrelizumab in PPMS trial, and I am aware of at least three other PPMS trials in development. 

Despite the advances in the treatment of PPMS mentioned above we have done many other things. For example, we have improved the recognition and diagnosis of the condition. Also, the symptomatic treatments for PPMS have improved. There are newer antispastic agents (Sativex, intrathecal baclofen, gabapentin), drugs and devices to improve walking (fampridine, functional electric stimulators, botox, better splints), better drugs and devices for bladder and bowel dysfunction, better drugs for pain, better drugs for osteopaenia, and this list goes on. We are improving outcomes by managing MS holistically and this is why the life-expectancy of PPMSers has improved substantially and is now only 3-4 years below what is expected for the general population; 25 years ago life expectancy was about 8 years lower.

So this commentator, who is clearly a cynic, should think a little more deeply and look at the facts before commentating.

Maybe the following quote from Bill Gates’ is apt: “we always overestimate the change that will occur in the next two years and underestimate the change that will occur in the next ten. Don’t let yourself be lulled into inaction”.

So if you have been diagnosed with PPMS in the last few years your outcome is so much better than it was 25 years ago and will continue to improve over the next 25 years. Please remember that innovation is relentless, even if you have PPMS, so never give up hope!

CoI: multiple

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