ECTRIMS2018 Time is Your Brain,

There is no doubt that some people do OK on CRAB (copaxone, rebif, avonex and betaferon) drugs, but many do not and there are a number of more effective agents out there. 

However there are consequences of not getting disease under control as shown at ECTRIMS 2018

Many people like the safety and the lack of monitoring requirements as “Give and forget” drugs. The lazy-risk averse neuro does not have much monitoring to do and so leaves you alone, whilst the MS monster can slowly chew up your brain reserve. We can all tolerate abit of nerve loss  and it happens to us all.  however it happens faster if your MS is not under control. Therefore “Give and forget” does not always mean “forget about your MS”. It may mean you actually “forget” as your brain reserve goes. 

This is clearly seen in the ocrelizumab trial data from the extension study. 

People were on beta interferon verses ocrelizumab. After two years every one switched on to ocrelizumab.

We all know that people on ocrelizumab did better and they had a slower loss of brain volume and progressed less. Once people switch from interferon to ocrelizumab, the rate of deterioration was the same, however three years on and the brain volume lost due to taking a low efficacy drug over the first too years remained.

Therefore, time is your brain.

Figures below are from the Hauser SL poster at the AAN 2018

The poster is from Hauser et al. 2018.

P590 – Long-term reduction of relapse rate and confirmed disability progression after 5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis
S.L. Hauser1, B. Brochet2, X. Montalban3,4, R.T. Naismith5, J.S. Wolinsky6, M. Manfrini7, M. Garas7, P. Villoslada8, F. Model7, S. Hubeaux7, L. Kappos9 

Background: The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week double-blind control period of OPERA I and OPERA II (NCT01247324; NCT01412333), and results for the 2-year follow-up of the pooled OPERA I and OPERA II open-label extension (OLE) period have previously been reported (Hauser SL, et al. AAN 2018; Abstract P1.366).
ObjectiveTo assess the efficacy of switching to or maintaining OCR therapy on clinical measures of disease activity and progression after 3 years of follow-up in the OLE period of the OPERA I and OPERA II Phase III trials in RMS.
MethodsAt the start of the OLE period, patients continued OCR (OCR-OCR) or were switched from interferon (IFN) β-1a to OCR (IFN-OCR). Adjusted annualised relapse rate (ARR), time to onset of 24-week confirmed disability progression (CDP24) and change in adjusted mean Expanded Disability Status Scale (EDSS) score from baseline were analysed.
ResultsOverall, 88.6% of patients who entered the OLE completed OLE Year 3. Among IFN-OCR patients, ARR decreased from 0.20 in the year pre-switch to 0.10, 0.08 and 0.07 at Years 1, 2 and 3 post-switch (p< 0.001, Year 1 vs pre-switch; p=0.31, Year 1 vs Year 2; p=0.56, Year 2 vs Year 3). OCR-OCR continuers maintained the low ARR through the year pre-OLE and the 3 years of the OLE period (0.13, 0.11, 0.08 and 0.07). OCR-OCR continuers versus IFN-OCR switchers had lower proportions of patients with CDP24 in the year pre-switch and Years 1, 2 and 3 of the OLE period (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1% and 16.1%/21.3%; p< 0.05, all difference comparisons). Changes in mean EDSS scores from baseline in OCR-OCR continuers versus IFN-OCR switchers will also be presented.
ConclusionsSwitching from IFN to ocrelizumab after 2 years at the start of the OLE period was associated with a rapid reduction in ARR. Both OCR-OCR as well as IFN-OCR patients maintained their robust reduction in ARR through the 3-year follow-up of the OLE period. After 5 years of follow-up, the proportion of patients with disability progression was lower in patients who initiated ocrelizumab treatment earlier (OCR-OCR), compared to patients who received initial IFN treatment (IFN-OCR switchers), showing that patients who initiated ocrelizumab 2 years earlier accrued significant and sustained reductions in disability progression compared to patients switching from IFN.

P588 – Long-term reduction in brain MRI disease activity and atrophy after 5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis
D.L. Arnold et al. 

Background: The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week double-blind control period (DBP) of OPERA I and OPERA II (NCT01247324; NCT01412333). Long-term brain tissue preservation is a critical objective in the treatment of multiple sclerosis (MS).

ObjectiveTo assess brain MRI measures of disease activity and atrophy after earlier vs delayed initiation of OCR at 5 years from core study baseline in Phase III trials in RMS.

MethodsAt end of DBP (Year 2), patients entered the open-label extension (OLE) and continued OCR (OCR-OCR) or were switched from interferon (IFN) β1a to OCR (IFN-OCR) and were analysed until Year 5. Brain MRI lesion activity (T1 gadolinium-enhancing [T1Gd+] lesions, new/enlarging T2 [N/ET2] lesions) and percentage change in whole brain volume (WBV), cortical grey matter volume (cGMV) and white matter volume (WMV) were analysed.

ResultsAmong IFN-OCR patients, the adjusted number of T1Gd+ lesions was 0.48 lesions/scan at Week 96 (DBP Year 2), and decreased to an unadjusted rate of 0.007, 0.004 and 0.004 at Week 144 (Year 3/OCR Year 1), Week 192 (Year 4/OCR Year 2) and Week 240 (Year 5/OCR Year 3), respectively. Similarly, the number of N/ET2 lesions decreased from an adjusted rate of 2.16 lesions/scan in Year 2 pre-switch to 0.33 in Year 3 (OCR Year 1) and decreased further to unadjusted rates of 0.063 and 0.038 in Years 4 and 5 (OCR Years 2 and 3). OCR-OCR continuers maintained low numbers of T1Gd+ and N/ET2 lesions at Years 3, 4 and 5 of OCR treatment. Earlier OCR-treated patients (5 years of OCR) vs delayed IFN-OCR switchers (3 years of OCR) had lower brain atrophy from core study baseline to the end of Years 3, 4 and 5 measured by WBV change (-1.31%/-1.51%, -1.58%/-1.87% and -1.87%/-2.15%; p< 0.01 for all); cGMV change (-1.47%/-1.56%, -1.73%/-1.91% and -2.02%/-2.25%; p=0.16, p< 0.01 and p< 0.01) and WMV change (-0.94%/-1.23%, -1.11%/-1.45% and -1.33%/-1.62%; p< 0.01 for all).

Conclusions: Patients with RMS switching at Year 2 from IFN to OCR had an almost complete and sustained suppression of MRI disease activity as measured by T1Gd+ lesions and N/ET2 lesions from Year 2 to 5. At 5 years from core study baseline, patients with 5-years’ continuous OCR treatment from randomisation experienced a lower brain atrophy as measured by change from baseline in whole brain, white matter and cortical grey matter volume compared with patients with a 2-year delayed OCR treatment start.

We still see the occassional placebo-controlled trials in relapsing MS, as the companies and regulators and the neuros associated with these studies accept that it is OK to do trials on Eastern Europeans. Whilst the trials may be cheaper to perform than in Western Europe. Alteratively the trials are performed against the least effective (Yes, the CRAB drugs) agents to show an effect of the new drug. Targeting the “low hanging fruit” (it is easy…as it is easier to pick the fruit at the bottom of a tree than the top) to beat in a trial is the current “ethical” approach to trials. It generally works although laquinimod took abit of beating when it went head to head with the CRAB…and failed

So we can ask, if it is not ethical to give nothing. Is it ethical to offer something that clearly does not stop the “MS shredder”.

A dillema, as it will be harder to find new treatments if we have to do head to head against the “big guns” (Most effective). Trials to show superiority of the new product or non-inferioity need to be large..hence expensive and slow to complete. So is this why the Western Funders (e.g. NIH) and Regulators “Give the Nod” (agree) to the placebo controlled studies.

It is not only ocrelizumab that slows brain shrinkage but other agents do it too. We know that natalizumab is very good at blocking new lesions and relapses. Does this benefit in the longer term. The Neuros from Sweden say Yes.

A. Manouchehrinia et al.

Background: Natalizumab, reduced relapse frequency and the risk of sustained disability progression in relapsing-remitting MS in the two-year pivotal clinical trials; however, the longer-term effectiveness of natalizumab is not established.

Objectives: To investigate the long-term effectiveness of natalizumab on physical and cognitive disability in a nationwide prospective cohort of relapsing-onset MS patients.

Methods: Patients prescribed natalizumab were followed in 58 neurology clinics across Sweden as part of a nationwide Phase 4 surveillance study. To be included persons must have had relapsing-onset disease, an MS onset after January 1st, 1995, and ≥ 12 months of natalizumab treatment. Expanded Disability Status Scale (EDSS) and symbol digit modality test (SDMT) scores were collected at baseline (initiation of natalizumab treatment), 6 and 12-months and annually thereafter. Rates of change on the EDSS, global age-related MS severity (ARMSS) and SDMT were compared between early- (treatment started ≤3 years from MS onset) and late-treated (>3 years after MS onset) patients. 
Second, disability rates in all natalizumab-treated individuals were compared to historic (MS onset pre-1995) and contemporary treatment-naïve cohorts and interferon [IFN] or glatiramer acetate [GA], treated individuals, using multilevel linear mixed effects models. 

Results: 2306 natalizumab-treated patients (901 early- and 1405 late-treated) were included. During the median follow-up of 72 months (interquartile range: 48-108), the EDSS score significantly increased by on average 0.03 score per-year (95% Confidence Intervals (CI): 0.02-0.04, P< 0.001). Conversely, the global ARMSS score showed improvement by -0.9 score (95%CI: -0.11–0.07) per-year. Late natalizumab-treated patients showed a more rapid increase in the EDSS score (additional increase of 0.06 score per-year (95%CI:0.04-0.08)) and decline in SDMT (additional decrease of -0.7 score per-year (95%CI: -1.2–0.17)) compared with early-treated patients. Natalizumab-treated individuals had significantly lower progression rates than the historic- (0.1 per-year (95%CI: 0.08-0.12), n=881) and contemporary-treatment naïve patients (0.08 per-year (95%CI: 0.05-0.12, n=266) and the IFN/GA-treated individuals (0.06 per-year (95%CI: 0.05-0.08), n=1062). 

ConclusionsNatalizumab was associated with reduced disability progression rate in relapsing-onset MS with even significantly higher effectiveness when initiated early.
Time is brain and ifeuro, would you want your brain shredded?

CoI: Multiple

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  • Can you pls write a small post of what we know to date on the brain atrophy rates (BVL loss) of Ocrel vs Natal vs Alem now that we have figures for all 3?

    • Lemtrada wins, but results use median atrophy, and given that growth is unlikely and atrophy could be theoretically be -99.9999% (death would have arrived much before then), one could posit that the median shows better results than the mean. Summary statistics would be best: number of Observations, interquartile range, median, and mean. Ocrevus uses an the means from an opaque stratified repeated measure, in attempts to decorrelate age location lesion load etc. It doesnt extrapolate to an observation like you or me in an informative way. Releasing raw data (patient id, brain measure), that would he more illuminating, but a simple median is more informative for an end consumer, and lemtrada has a normal brain atrophy rate in RRMS, by the 3rd and 4 and 5th year. Ocrevus gets to a rate that is still about 50% than a healthy person, but that is much better than the 200% to 1000% that an untreated MS persob experiences.

  • Please, do you have data regarding brain atrophy rates when treated with Cladribine and how this compares with Ocrelizumab or Natalizumab? I assume that Alemtuzumab is the DMT with the most efficacy to reduce brain atrophy?

  • Yes it is unethical to put people nowadays on CRUB drugs. It would be nice to have a blog-post on brain atrophy, summarizing all the findings of the modern drugs. However, the term "modern" might be misleading, most if not all effective drugs are cancer drugs, decades old, cladribine first approved in 1993, rituximab in 1997 and alemtuzumab in 2001. It's time to do some real science and find the disease mechanism and cure and not just apply the sledge-hammer approach. Nevertheless, this seems no impossible, as the old cancer drugs have secured the market for the next decade.

  • Returning to the reading of the blog last month I stayed away from reading this space.

    Returning now since I am in a country on the verge of electing a government in Brazil of facist bias, and that can put an end to the Brazilian public health service (called SUS), one of the largest in the world.
    Even with many problems, SUS can treat people with MS.
    I dreamed of a future here in the Brazil where SUS could offer Cladribine, Rituximab and Natalizumab as a broad treatment for MS instead of CRABS.

    Fear of what may be in the future of people with multiple sclerosis in Brazil…

  • 7-year outcomes in MS patients of African descent treated with alemtuzumab: follow-up of CARE-MS I and II (TOPAZ Study)

    60% of patients had stable/improved EDSS scores from baseline to Y7. In Y7, 63% were free of MRI disease activity; 94% were free of new Gd-enhancing lesions and 63% were free of new/enlarging T2 hyperintense lesions. Median percent cumulative brain volume loss (BVL) from baseline over 7 y was -0.75%; median yearly BVL in Y7 was 0.28%. There were no serious thyroid AEs or malignancies through Y7; no new cases of immune thrombocytopenia or nephropathy were seen. The safety profile was consistent with the overall alemtuzumab study population.

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