Disability Progression in Secondary Progressive Multiple Sclerosis (SPMS)
Hans-Peter Hartung , Douglas Arnold, Mark Freedman , Eva Havrdova , Douglas Jeffery , Raju Kapoor , Aaron
Miller , Finn Sellebjerg , Haihong Li, Nisha Lucas, Diego Cadavid, Nolan Campbell, Pei-Ran Ho, Deborah
Objective: To investigate long-term (>2 years) effects of natalizumab treatment in the ASCEND open-label
Background: During ASCEND’s 2-year randomized treatment period, natalizumab did not delay disability
progression in SPMS patients with advanced disease assessed by the primary composite endpoint (Expanded
Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-Hole Peg Test [9HPT]), but did slow
progression on the 9HPT (upper-limb) component.
Design/Methods: Patients who completed the 2-year, randomized, placebo-controlled treatment phase and
entered the extension phase received open-label natalizumab. Original treatment assignments remained blinded
to investigators and patients throughout the extension. Disability progression was assessed for up to 3 years
using the primary composite endpoint.
Results: Of 888 randomized, dosed ASCEND patients, 566 (63.7%) participated in the open-label extension
(switched-from-placebo: n=274, median follow-up=156.9 weeks; natalizumab-continuers: n=292, median followup=160.4
weeks). Baseline characteristics and disease history were similar between groups and consistent with
the overall ASCEND population. Fewer natalizumab-continuers than switched-from-placebo patients were
composite endpoint progressors (52% vs 61%; adjusted odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.47-
0.94; P=0.02). Natalizumab reduced 9HPT progression (19% natalizumab-continuers vs 28% switched-from placebo;
adjusted OR: 0.59; 95% CI: 0.39-0.88; P=0.01). T25FW and EDSS progression comparisons favored
natalizumab (T25FW, adjusted OR: 0.80; 95% CI: 0.57-1.12; P=0.20; EDSS, adjusted OR: 0.73; 95% CI: 0.48-
Conclusions: The ASCEND open-label extension showed clinically meaningful benefits of natalizumab on
disability progression in advanced SPMS patients. Consistent with 2‑year results, the largest treatment benefit
was seen on preserving upper-limb function (9HPT), but preservation of ambulatory function (T25FW and EDSS)
was also observed, leading to overall benefit on the primary composite endpoint. These results suggest that,
while some benefits are evident after natalizumab initiation, full benefits on disability progression, particularly
lower-limb function, in advanced SPMS patients may not be evident until after longer treatment duration.
Natalizumab treatment in progressive MS failed or did it? If you look at the pre-described endpoint if failed, but thinkhand and the conclusion is diferent and it worked, so the length-dependent hypothesis holds up.
Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.Giovannoni G, Cutter G, Pia-Sormani M, Belachew S, Hyde R, Koendgen H, Knappertz V, Tomic D, Leppert D, Herndon R, Wheeler-Kingshott CA, Ciccarelli O, Selwood D, di Cantogno EV, Ben-Amor AF, Matthews P, Carassiti D, Baker D, Schmierer K.Mult Scler Relat Disord. 2017 Feb;12:70-78.
The longer nerve tracts get more damage and so hand function is saved, but if you bring therapeutic lag, which means trials need to be longer we see if the trial would have been three years then the trial would be considered positive.
When this paper appears I am sure ProfG will pipe-up with “I told you so”
However, further evidence that people with progressive MS should have access to DMT