|Year : 2022 | Volume
| Issue : 4 | Page : 577-578
ALS treatment- We Still Await the “Magic Cocktail”
Jasmine Shimin Koh1, Su Rong Fam2, Peng Soon Ng1, Thirugnanam Umapathi1
1 Department of Neurology, National Neuroscience Institute (Tan Tock Seng Hospital Campus), Jalan Tan Tock Seng, Singapore, Singapore
2 Department of Neuroscience Nursing, National Neuroscience Institute (Tan Tock Seng Hospital Campus), Jalan Tan Tock Seng, Singapore, Singapore
|Date of Submission||01-May-2022|
|Date of Decision||01-May-2022|
|Date of Acceptance||02-May-2022|
|Date of Web Publication||04-Aug-2022|
11 Jalan Tan Tock Seng, Singapore - 308 433
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Koh JS, Fam SR, Ng PS, Umapathi T. ALS treatment- We Still Await the “Magic Cocktail”. Ann Indian Acad Neurol 2022;25:577-8
Edaravone (MCI-186), a free-radical scavenger of peroxyl radicals and peroxynitrites, has been shown to inhibit motor neuron death by reducing oxidative stress in animal studies., A randomized, double-blind, placebo-controlled study looked at the efficacy and safety of edaravone in patients with amyotrophic lateral sclerosis (ALS) in 31 Japanese institutions., Intravenous edaravone 60 mg was given daily for two weeks, followed by a two-week drug holiday. The cycle was repeated five times for the next 24 weeks. In cycles 2–6, edaravone was given for ten days, followed by a two-week drug holiday. The benefits, measured by the change in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline, were modest at best. The strict inclusion criteria were based on the post-hoc analysis of a prior Phase 3 negative trial and ensured patients had mild and early disease, that was less than two years duration; were independent in activities of daily living (Japanese ALS severity grade 1 or 2), scored not worse than 2 points on all 12 items of ALSFRS-R; and had a forced vital capacity ≥80%. To ensure patients had “active disease,” there had to be a 1–4 points decrease in ALSFRS-R score in the 12 weeks prior to randomization. This study compared the least mean square difference in the ALSFRS-R scores (i.e., average of the mean ALSFRS-R scores) at 24 weeks against baseline in both groups. For those who completed cycle 3 but had missing outcome data at week 24, the study applied the last observation carried forward (LOCF) method with sensitivity analysis and a mixed-effects model to compute the primary endpoint. While the study method accounted for nonlinear disease progression, it assumed both groups progressed at the same rate, which was unlikely, and any difference in the primary endpoint between the groups might therefore been amplified. An open-label 24-week extension of this study appeared to show maintenance of the benefits in those receiving edaravone. Another open-label trial that used the same inclusion criteria suggested edaravone was beneficial in slowing down disease progression even after receiving six months of placebo, with the efficacy maintained for up to one year.
The outcome of a recent study evaluating edaravone's effect on less selected ALS patients managed in a real-world setting did not replicate these findings. This propensity score-matched observational cohort study evaluated 116 definite or probable ALS patients (El Escorial criteria) at 12 sites in Germany. The patients were administered intravenous edaravone and riluzole at the clinician's discretion. The control group received standard therapy with riluzole. Both groups were matched for the period of diagnosis, site and age at onset, disease duration, and baseline ALSFRS-R score. The primary endpoint was ALS progression, measured using monthly decreases in ALSFRS-R score computed via linear regression. For those who completed cycle 4 but had missing outcome data at week 24, the primary endpoint was measured at the last follow-up (i.e., no extrapolation was made using the LOCF method). The secondary endpoints were survival probability, time to ventilation, safety, and the change in disease progression rates from before baseline to end of treatment, measured using the ALSFRS-R score points lost since ALS onset. No significant difference in disease progression was noted between those treated with edaravone for a median of 13.9 months and those who received riluzole for a median of 11.2 months (-0.91/month vs. -0.85/month, P = 0.37). There was no significant difference in secondary endpoints. No benefit was found in the sub-group of patients who would have satisfied the inclusion criteria of the original Japanese study either. A small number of patients experienced adverse events, generally quite innocuous. Although this study had inherent limitations (observational retrospective study, non-random-allocation, missing data, heterogeneous follow-up period, and assumption of linear disease progression in both groups), it cast doubt on the efficacy of edaravone outside the strict stipulations of the earlier studies.
In this issue of the journal, Samadhiya et al. compare the disease progression in patients on edaravone and riluzole combination treatment with those on riluzole alone at an Indian institution. Their findings suggest that combination therapy is better at slowing the disease over six months. This is a small, single-center study with a 15–20% drop-out rate. It assumes that patients in both groups progress at the same rate; this is unlikely given that their baseline modified Rankin scale (mRS) is different.
However, its major limitation is the lack of blinding of the patients and the investigators. The components of mRS, ALSFRS-R, and Japanese ALS severity scores are quite subjective reports of functions and prone to bias. For example, salivation ALSFRS-R score 3 is, “Slight but definite excess saliva in mouth; may have night-time drooling”; while 2 is, “Moderately excessive saliva; may have minimal drooling”. Furthermore, the above-mentioned scales are ordinal in nature. To handle them as interval scales with intermediate decimal points may not be accurate. For instance, a worsening of mRS between 1 to 2 is not equivalent to the quantum change between 2 to 3. Finally, differences in these scores that were detected in clinical trials, albeit statistically significant, may not always translate to a congruent degree of clinical significance. Even in the seminal Japanese study, the clinical significance of the difference in ALSFRS-R score between active and placebo groups of 2.5 points was uncertain when respiratory function and muscle strength did not differ.
One important aspect not studied systematically in these studies is the burden of edaravone treatment relative to its efficacy. Edaravone is costly. The treatment protocol is cumbersome, requiring prolonged hospitalization or multiple-day visits, which is likely to impact considerably on patients' already redacted quality of life (QOL). We examined this issue in 11 ALS patients (ethics approval CIRB 2015/2030) treated with edaravone at our institution over a 6-year period. The patients were functionally independent prior to edaravone treatment (median mRS 2, range 1–2). Four patients fulfilled all criteria defined in the above-mentioned Japanese study. Ten patients received riluzole. At six months of edaravone treatment, there was no significant decline in ALSFRS-R; none were ventilator-dependent, and median mRS increased to 4 (range 2–4). The average number of hospitalization days for edaravone treatment was 65.5 (64–82) days. Average treatment cost ranged from $27,036 to $36,804 SGD ($19,926 to $27,126 USD). Edaravone treatment is estimated at $15,000 USD/patient in the USA. Such costs are certainly prohibitive for the limited health budgets of developing countries. One could argue that these resources could be better utilized to develop palliative and end-of-life protocols that improve ALS patients' QOL.
Notwithstanding the cost and burden of treatment, we believe the future of ALS therapeutics, like cancer therapy, lies in careful phenotyping, using a combination of biological and genetic markers, to identify subtypes that may respond to different drug combinations. We also need to delineate robust and clinically meaningful outcome measures. ALS research could leverage the tremendous developments in bioinformatics, data science, and artificial intelligence to achieve these aims. Such endeavors would inevitably require global cooperation to achieve the requisite quantum and rigor of data.
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