Late Breakers
ECTRIMS 2025 is now underway.
Sorry it is a post on CD20 and I know some of you are abit bored by this but this actually about work we have done and it is relevant that this is ocrelizumab, if we did the same study with Natalizumab we would get the same result…Indeed when you analyse the data of the failed ASSEND|TRIAL IN progressive MS and have hand function as the endpoint you have success too. So this is another example of success when you use your brain to think and learn from the biology.
Many years ago profG wrote a paper on the length-dependent axonopathy saying that the longer nerve tracts will accumulate damage more rapidly than shorter nerve tracts. This was in part based on the view from the beasties in that the tail went first, then the hind legs and then more seldomly the front legs. So the idea was that the neurological reserve to tolerate damage would be exhausted first in the tail, then the hindlimbs and so it says the legs will go before the arms in MS. So the reserve will go in the legs before the arms and so whilst you may not be able to stop damage to the legs you still maybe able to save the arms and the head.
This is the basis for CHARIOT-MS which ProfK is leading.
This is shown in ORATORIO Hand or O-hand as we know it.
In ECTRIMS 2015 in London we made real push to get this concept into people heads. We wanted to do studies to show it.
It is easier and quicker to do this with pharma because if they decide to do it they have the cash, and people with vision, but if you want to do it as an academic you have to spend ages getting support to do it and getting round the luddites that keep the status quo. As you know I am not a Status Quo fan
So the idea was that if you have hand function as the main endpoint you can get a success when you fail if you have leg function as an endpoint. If this had been done, you would of a had drugs approved for progressive MS years ago. It says the two stage process of relapse and progression as separate entities believed by some…. is ****ocks. It tells us that the processes driving relapse have a effect on progressive MS …it says PIRA as defined in many current studies is also jajce and so we should not give up on anyone with MS, because MS is inflammatory from the beginning to end and it is also neurodegenerative from beginning to end. This study has people with more advanced MS than any previous pharma study. So rather than just doing EDSS the regulators now accept hand function as part of the endpoints and we are seeing success in progressive MS….we will see it again with other agents I am sure.
It is not the answer and we need treatment for the progressive parts of MS. However it says to me any study on progression that does not deal with the inflammatory component is going to struggle. Sadly this is not central to the design of OCTUPUS. So as I have said over and over again trial design is key.
In this study there is also a positive effect on leg function, but the effect on hand function was greater. This is something positive that came from PROMISE 2010 and before and it is IMPACT as changing how regulators think will help agents appear for progressive MS. Will walking round with balloons saying 95% at ECTRIMS be seen as having impact?. This was figure was the fact that it was important to 95% of people with MS to save hand function
Thomson A, Horne R, Chapman C, Bharadia T, Burke P, Colwell E, Harrington M, Boskovic B, Stennett A, Baker D, Giovannoni G, Schmierer K. Engaging a community to focus on upper limb function in people with multiple sclerosis: the ThinkHand campaign case study. Res Involv Engagem. 2024;10(1):62. doi: 10.1186/s40900-024-00586-y.
Abstract Number: 104/O128 Ocrelizumab vs placebo in primary progressive MS: efficacy and safety results of the Phase IIIb ORATORIO HAND study Gavin Giovannoni *
Introduction: ORATORIO is the only Phase III trial in people with primary progressive multiple sclerosis (pwPPMS) that showed superiority of a treatment, ocrelizumab (OCR), vs placebo (PBO) in delaying disability progression. The impact of OCR in older and more disabled pwPPMS is not fully understood, particularly in preventing worsening of hand function—critical for self-care and maintaining independence.
Objectives/Aims: ORATORIO-HAND (NCT04035005) is a Phase IIIb, multicentre, randomised, double-blind, PBO-controlled trial investigating the efficacy and safety of OCR in pwPPMS including, for the first time, more-advanced PPMS.
Methods: Adult pwPPMS aged ≤65 years (y) with an Expanded Disability Status Scale (EDSS) score of 3.0-8.0 were randomised 1:1 to OCR 600 mg or PBO every 6 months for 144 weeks (wk) or until ≥340 progression events were observed, whichever occurred first. The primary endpoint was a composite of time to onset of 12-wk confirmed disability progression (12W-CDP) in 9-Hole Peg Test (CDP-9HPT ≥20% worsening from baseline) or EDSS (CDP-EDSS) in all randomised patients (pts) and a subset of pts with MRI activity during screening or at baseline.
Results: OCR (n=505) and PBO (n=508) pts, baseline median (range) age was 48 (18-66) vs 47 (22-66) y and median (range) EDSS was 6.0 (3.0-8.0) vs 6.0 (2.5-8.0). Median treatment duration was 143.7 and 143.4 wk. The percentage of OCR and PBO pts with 12W-CDP on the composite endpoint was 32.7% vs 40.4% (hazard ratio [HR] [95% CI]: 0.70 [0.57-0.86]; risk reduction [RR], 30%; P=0.0007), 16.7% vs 24.9% on 9HPT (RR, 41%; P=0.0002) and 23.0% vs 30.8% on EDSS (RR, 33%; P=0.0013). In the MRI-active subset, the percentage of ptswith 12W-CDP on the composite endpoint was 26.8% vs 45.9% (HR [95% CI]: 0.45 [0.31-0.64], RR, 55% P<0.0001), with a significant RR observed in CDP-9HPT (62%) and CDP-EDSS (59%). Adverse events (AEs) in OCR vs PBO arms were: all AEs, 74.9% vs 71.1%; serious AEs, 12.8% vs 13.2%; infusion-related reactions, 20.8% vs. 4.3%; malignancies, 1.0% vs 0.6%; infections, 48.4% vs 44.7%; serious infections, 6.3% vs 5.3%. AEs leading to treatment withdrawal were seen in 3.0% (OCR) and 2.4% (PBO) of pts. Conclusion: In a large PPMS population that included pts with more advanced disease, OCR was superior to PBO in delaying overall disability progression (EDSS) and worsening of upper limb function (9HPT). The AE profile was balanced between both arms, aligning with the known OCR safety profile.
Source: multiple-sclerosis-research.org