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.
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).
To 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.
At 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.
Overall, 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.
Switching 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.
D.L. Arnold et al.
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).
To 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.
At 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.
Among 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).
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.
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.