Considerations for pharmacotherapy use in patients with amyotrophic lateral sclerosis: the earlier it starts, the better the results

KEYWORDS:

• ALSFRS-R
• disease duration
• edaravone
• methylcobalamin
• prognosis
• riluzole

1. Introduction

Amyotrophic lateral sclerosis (ALS) is a degenerative disease affecting the upper and lower motor neurons, leading to bulbar and spinal muscle weakness. Disease progression is more rapid than in most other neurodegenerative disorders, and patient prognosis is poor because most patients suffer from respiratory paresis in the advanced stages of the disease. Major genetic causes of ALS include mutations in SOD1 [1] and TARDBP [2], and an abnormal hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) [3]. Despite extensive research into the molecular pathomechanism of ALS, clinical treatment options remain limited, with approved pharmacological treatment restricted to two drugs, riluzole and edaravone. Confirmative clinical trials of these drugs are shown in Table 1. Riluzole modulate glutamatergic neuronal transmission [4], and edaravone is a potent scavenger of reactive oxygen species [5].

Table 1. Key trials for the treatment of amyotrophic lateral sclerosis.

Drug	Number of patients	ALS diagnostic criteria	Disease duration at enrolment	Outcome measure	Main results	Year	Reference
Riliuzole (100 mg)	155 (riluzole 77, placebo 78)	Probable or definite	≤5 years	Survival rate (%) at 12 months	74% vs 58% survival at 12 months, p = 0.014	1994	[6]
Riluzole (50, 100, 200 mg)	955 (100 mg riluzole 236, placebo 242)	Probable or definite	≤5 years	Survival without tracheostomy (OR), 100 mg riluzole vs placebo at 18 months	Odds ratio: 0.79 (unadjusted, p = 0.076), 0.65 (adjusted, p = 0.002)	1996	[8]
Edaravone 60 mg/day × 14 days in 28 days (1st cycle) or 10 days in 28 days (2nd cycle and thereafter)	205 (edaravone 101, placebo 104)	Definite, probable, or probable laboratory-supported	≤3 years	Change in ALSFRS-R score	Group difference: 0.65 points (−0.90 to 2.19, p = 0.411)	2014	[12]
Edaravone 60 mg/day × 14 days in 28 days (1st cycle) or 10 days in 28 days (2nd cycle and thereafter)	137 (edaravone 69, placebo 68)	Probable or definite	≤2 years	Change in ALSFRS-R score	−5.01 (SE 0.64) in edaravone, −7.50 (0.66) in placebo, group difference: 2.49 (0.99–3.98), p = 0.0013)	2017	[11]

Abbreviations: ALS: amyotrophic lateral sclerosis; OR: odds ratio; ALSFRS-R: revised ALS functional rating scale; SE: standard error.

2. Approved drugs for ALS

2.1. Riluzole

A clinical trial of riluzole reported statistically significant beneficial effects on prognosis in patients with ALS [6], and it is the first drug approved by the U.S. Food and Drug Administration (FDA) in 1995. In the trial, survival analysis revealed that prognosis was significantly improved in the riluzole group compared with the placebo group, even in a stratified group of patients with bulbar-onset ALS, in which disease progression is more rapid than in patients with limb-onset ALS [7]. A subsequent confirmative clinical trial demonstrated that the hazard ratio for survival without tracheostomy was lower in a riluzole treatment group than in a placebo group, with statistical significance demonstrated in Cox regression analysis with adjustment for prognostic factors [8]. Taken together, the efficacy of riluzole demonstrated in these two clinical trials can be considered statistically significant but modest.

Fang and his colleagues investigated whether riluzole provides efficacy in early stage, in late stage, or throughout the clinical course of ALS. They performed a large-sized retrospective analysis consisting of 959 patients enrolled in previous clinical trials of riluzole. They compared time of remaining same stage between placebo, 50, 100, and 200 mg riluzole in stage 2, stage 3, and stage 4. As a result, riluzole prolonged the time of remaining stage 4, suggesting riluzole may provide effects even in advanced stage of ALS [9]. However, in a population-based study, the efficacy of riluzole was confirmed in patients with bulbar-onset ALS, but the effect was unfortunately shown to diminish within 1.5 years [10]. The efficacy of riluzole was further investigated in a retrospective study of 148 patients who received riluzole and 327 patients who did not receive riluzole [11]. In this non-randomized analysis, survival time was 3.07 (2.73–3.41) years (median [95% confidence interval]) in riluzole-treated patients and 2.25 (2.03–2.48) years in non-riluzole-treated patients, with a statistically significant difference between the groups. In the bulbar-onset subgroup, median survival time was 2.19 (1.91–2.48) years and 1.84 (1.29–2.38) years in the riluzole and non-riluzole groups, respectively, although the difference was not statistically significant. In the limb-onset subgroup, median survival time was 3.61 (2.97–4.25) years in the riluzole group and 2.62 (2.12–3.13) years in the non-riluzole group, and the difference was statistically significance [11].

2.2. Edaravone

Edaravone has recently been shown to suppress worsening of motor weakness in patients with ALS in a phase III clinical trial (MCI186-19 study) [12], and was approved by Japan Pharmaceuticals Medical Devices Agency in 2015 and by the U.S. FDA for the treatment of ALS in 2017. In Europe, the following criticism has been raised in European Network for the Cure of ALS; the efficacy of edaravone is proved in only one clinical trial; and edaravone is administered intravenously; and the costs are high. The drug has not been approved in the Europe.

Edaravone is a radical scavenger [5] that has previously been approved for the treatment of cerebral embolism. The first confirmatory phase 3 clinical trial of edaravone demonstrated that it improved the change in revised ALS functional rating scale (ALSFRS-R) score compared with placebo in patients with ALS, although the difference unfortunately did not reach statistical significance (MCI186-16 study) [13]. However, a post-hoc subgroup analysis indicated that edaravone treatment may have a significant effect in patients diagnosed as having probable or definite ALS according to El Escoria criteria and with a disease duration of 2 years or less [13]. The MCI186-19 study, which was completed in 2014, was designed to investigate the effect of edaravone on motor worsening in patients with definite or probable ALS and with a disease duration of 2 years or less. The results of the study showed that edaravone provided a statistically significant improvement in ALSFRS-R score change.

Both of these well-designed trials had a 12-week observation period prior to randomization and a 24-week two-arm treatment period. Patient age, sex, disease duration, and ALSFRS-R score at baseline were highly similar between the two trials. What, then, contributed to the differences in outcome? The ALS subtype by El Escoria criteria, as mentioned above, may have been a contributing factor. Patients with probable laboratory-supported ALS were excluded from the more recent trial (MCI186-19 study). In the MCI186-16 study, the change in ALSFRS-R score in the placebo arm was −8.7, −6.1, and −4.0 points in the definite, probable, and probable laboratory-supported ALS subgroups, respectively, and the group difference between edaravone and placebo was 2.0, 0.9, and 0.4 in the definite, probable, and probable laboratory-supported ALS subgroups, respectively. In the MCI186-19 study, the change in ALSFRS-R score was −7.5 in the placebo arm, which was consistent with the data for the definite and probable ALS subgroup patients in the MCI186-16 study. The change in ALSFRS-R score in the edaravone-treated arm was complex, however; values of −6.7 and −5.2 were observed in the definite and probable ALS subgroups, respectively, in the MCI186-16 trial while a value of −5.01 was reported in the MCI186-19 trial for definite or probable ALS patients, suggesting that edaravone showed greater efficacy in the MCI186-19 trial than in the MCI186-16 trial. This difference in effect may potentially be explained by the difference in disease duration at baseline between the two trials. In the MCI186-16 trial, the maximum disease duration was 2.9 years, but the MCI186-19 trial included patients with a disease duration of 2 years or less, suggesting that earlier imitation of edaravone treatment may lead to a better outcome.

An open-label extension of the MCI186-16 study was subsequently reported [14], and patients who participated in both the blinded phase and the open-label extension were randomized to edaravone-edaravone treatment for 24 weeks and to placebo-edaravone treatment for 24 weeks. Interestingly, ALSFRS-R score was improved to a greater extent in the edaravone-edaravone treatment group than in the placebo-edaravone group at the end of the open-label extension phase, although this result did not reach statistical significance. Similarly, %FVC (forced vital capacity), modified Norris Scale, and ALSAQ-40 (40 items ALS Assessment Questionnaire) scores were better in the edaravone-edaravone treatment group than in the placebo-edaravone treatment group, although the differences were again not statistically significant. In addition, Kaplan–Meier curves of cumulative survival rate without a predefined hard endpoint, including death, tracheostomy, mechanical ventilator use, tube feeding, and complete loss of function, showed an improvement in the edaravone-edaravone treatment group compared with the placebo-edaravone treatment group, though without statistical significance. These data suggest that edaravone may have greater efficacy if treatment is initiated at an earlier stage. In early stage of the disease surviving motor neurons are more abundant than in the advanced stages, and therefore, early-start edaravone may rescue more neurons.

In both the MCI186-16 and MCI186-19 trials, approximately 90% of patients also received riluzole, indicating that concomitant treatment with riluzole and edaravone should be started at an earlier stage following clinical diagnosis of ALS.

3. Conclusions

Riluzole and edaravone are now available for clinical pharmacological treatment for ALS. Their effects are modest in clinical trials; however, the earlier initiation of combination therapy of these two drugs is recommended.

4. Expert opinion

Clinically available interventions are limited to the two drugs, riluzole and edaravone, and the effects against worsening motor deterioration are very limited. Though ALSFRS-R has a strong correlation with life prognosis or survival time to tracheostomy [15], it is not a hard endpoint. In clinical trials of edaravone the primary outcome measure was changes in ALSFRS-R score that is a surrogate marker instead of hard endpoint. Therefore, large-sized trials with a hard endpoint outcome measure will be required in evaluation for edaravone in the future.

Another point is progression of the disease, because it is associated with initial speed of the progression. Patients with small score worsening in ALSFRS-R in the initial stage tend to have long survival time [16,17]. In this point of view, the sensitivity analysis by initial worsening of ALSFRS-R may provide informative data, and statistical regulation of initial slope in ALSFRS-R can provide more precise evaluation in future clinical trials. In addition, early start of pharmacological intervention should be considered especially in rapidly progressive patients.

Both drugs have no symptomatic effects but may have ‘disease-modifying effects.’ Taking the results of the randomized blind phase (MCI186-16) and the succeeding open-label trial of edaravone together, edaravone may provide disease-modifying effect on worsening of motor weakness of ALS.

Very recently the trial result of ultra-high-dose methylcobalamin was published [18]. There were no significant differences in ‘survival time to tracheostomy or death’ or ALSFRS-R changes between methylcobalamin (25 and 50 mg) and placebo. The authors suggested that 50 mg methylcobalamin may provide beneficial effects in a post-hoc subgroup of patient with disease duration of 1 year or less. However, in their statistical plan predefined 11 subgroup analyses (stratified by age, sex, initial symptoms, family history, disease duration (18 months), %FVC, %FVC changes in the pretrial period, riluzole use, El Escoria diagnostic criteria (clinically definite, clinically probable, clinically probable laboratory supported), ALS severity, change in total ALSFRS-R score in pretrial period were planned, and therefore, the data should be considered with multiple comparisons. According to the supplementary table e-2 of the paper, there were no difference in the subgroup of patients with disease duration ≤ 18 months (hazard ratio 0.90 [95% confidence interval 0.61–1.32]). Methylcobalamin is a vitamin and can be a low-cost intervention, but the future cost of ultra-high-dose methylcobalamin is uncertain.

The result of MCI186-19 trial suggests that the effect of edaravone against motor weakness can be detected given the treatment is started within 2 year from the disease onset. Because the speed of neurodegeneration is rapid in ALS, early start of combination therapy of riluzole and edaravone is recommended.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patent receiving or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We thank Clare Cox, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Additional information

Funding

This paper was not funded.