Neuroprotection in Progressive MS Will Require Combination Approach

Author(s):

Data from the MS SMART trial, which may serve as a template for simultaneous testing of multiple DMTs, suggest that exclusively targeting axonal pathobiology is inadequate to prevent neuroaxonal loss.

Jeremy Chataway, MA, PhD, FRCP, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College Foundation NHS Trust, London and St Marys Hospital

Jeremy Chataway, MA, PhD, FRCP

In a phase 2b assessment which, importantly, may act as a template for simultaneous testing of multiple disease-modifying therapies (DMTs) in neurological medicine, investigators observed that the exclusive targeting of axonal pathobiology in multiple sclerosis (MS) with amiloride, fluoxetine, or riluzole is not enough to slow or prevent neuroaxonal loss.

The MS SMART trial (NCT01910259) evaluated the potential for neuroprotection in patients with secondary progressive MS during treatment with 5-mg amiloride (n = 99), 20-mg fluoxetine (n = 96), 50-mg riluzole (n = 99), or placebo (n = 99). All told, over the course of 96 weeks, there were no differences between active treatment and placebo in the rate of volumetric MRI percentage brain volume change (PBVC).

The difference between amiloride and placebo was 0% (95% CI, −0.4 to 0.5; P = .99); fluoxetine and placebo was −0.1% (95% CI, —0.5 to 0.3; P = .86), and riluzole and placebo was −0.1% (95% CI, —0·6 to 0·3; P = .77). The change for amiloride was 1.3%, for fluoxetine was —1.4%, for riluzole was –1.4%, and placebo was –1.3%.

“These findings argue for investigation of different mechanistic targets and future consideration of combination treatment trials,” Jeremy Chataway, MA, PhD, FRCP, consultant neurologist, National Hospital for Neurology and Neurosurgery, University College Foundation NHS Trust, London and St Mary’s Hospital, and colleagues detailed.

The multiarm study was parallel-group, randomized, and double-blinded, conducted at 13 clinical neuroscience centers in the UK. The patients were aged 25 to 65 years and were not on DMT. All patients had an Expanded Disability Status Scale (EDSS) score of 4.0 to 6.5.

“Multiarm trials are feasible and efficient in neurodegenerative diseases. They have the potential to examine promising experimental and early-phase agents in a timely fashion,” Chataway et al. wrote. “The results of our study have implications for future experimental paradigms. This style of approach is necessary to accelerate treatment discovery in an area in which limited progress has been made.”

The secondary outcomes—new or enlarging T2 lesions at 96 weeks and PBVC at 24 weeks—were indicative of no evidence of a therapeutic effect.

At 24 weeks, the PBVC for patients administered fluoxetine was greater than placebo (difference, —0.31; 95% CI, –0.60 to –0.02; P = .032), but no other groups. There was no difference between the active groups and placebo at 24 weeks and at 96 weeks. The mean number of new or enlarging T2 lesions at 96 weeks was 3.0 for the placebo group (standard deviation [SD], 6.9; median, 0 [IQR, 0—2]). The results were similar for amiloride (rate ratio [RR], 1.2; 95% CI, 0.8–1.8; P = .29) and for riluzole (RR, 1.0; 95% CI, 0.6—1.5; P = .81), while fluoxetine had fewer compared with placebo (RR, 0.5; 95% CI, 0.3—0.9; P = .012).

The results, Chataway and colleagues wrote, don’t support amiloride, fluoxetine, and riluzole’s effectiveness in reducing disease progression for secondary progressive MS. This suggests that, in light of the need for DMTs for progressive MS, research should shift towards “combinatorial strategies or stratification based on a greater resolution of relevant pathobiology at the level of individual patients,” they detailed.

Although 5 of 60 clinician-reported and patient-reported outcome comparisons against placebo were significant (P <.05), Chataway and co. wrote this was similar to what they “would expect” due to random chance.

Ultimately, 11% (n = 51) of the 445 total patients had at ≥1 relapse during the study, with 14% (n = 16) in the amiloride group, 9% (n = 10) in the fluoxetine group, 10% (n = 11) in the riluzole group, and 12% (n = 14) in the placebo group. Time to first relapse was similar between all 3 therapies—amiloride (hazard ratio [HR], 1.14; 95% CI, 0.56—2.35), fluoxetine (HR, 0.74; 95% CI, 0.33–1.66), or riluzole (HR, 0.78; 95% CI, 0.35–1.73)—compared with placebo.

As well, the Timed 25-Foot Walk test did not differ for amiloride (HR, 0.82; 95% CI 0.61—1.12), fluoxetine (HR, 0.81; 95% CI, 0.59–1.10), or riluzole (HR, 0.84; 95% CI, 0.61–1.13).

Chataway and colleagues noted that the mechanisms of action amiloride, fluoxetine, and riluzole were likely to be accompanied by off-target effects. Mainly, they target distinct possible axonal pathobiological features involved in the neurodegeneration of progressive MS. Although the processes of each of these evaluated treatments represent plausible targets for neuroprotection, the group acknowledged the odds that additional pathological processes can be involved in disease progression.

“Thus, several explanations could account for why amiloride, fluoxetine, and riluzole did not show efficacy in our study, including (but not restricted to) the ultimate relevance of the dynamic in-vivo disease processes primarily targeted by these 3 drugs,” they wrote. “Indeed, our findings expose our incomplete knowledge of the pathobiology of secondary progressive MS.”

REFERENCE

Chataway J, De Angelis F, Connick P, et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomized placebo-controlled trial. Lancet Neurol. Published online January 22, 2020. doi:10.1016/s1474-4422(19)30485-5.