What can we learn from the edaravone development program for ALS?

Abstract

Edaravone’s development into an ALS therapeutic has been a process which began with preclinical studies regarding its potential in targeting ALS. Despite edaravone’s inability to show benefit in a general ALS population, an important post-hoc analysis showed that a clinical subset of patients had benefit. Most importantly, a subsequent study examining the capacity of edaravone to have benefit in this specific subset of ALS patients was successful in meeting its primary outcome measures. Questions regarding whether the dosing regimen could be simplified or improved, the duration of the effects, and the timing of the potential treatment to different stages of disease remain to be answered. However, the benefit of this compound in delivering a meaningful therapy to ALS patients and the lessons learned with regard to its development should widen interest in clinical research so that additional strategies for treating ALS may become available to patients.

Keywords:

• Therapy
• drug
• clinical trial
• motor neuron disease

Introduction

The supplement published in this issue of ALS-FTD on the use of edaravone for the treatment of ALS is a synopsis of a preclinical and clinical programme which has spanned three decades from its early development as a drug used to treat acute cerebral ischaemia (1) through to a recent phase III study (2) in ALS demonstrating efficacy for its primary outcome measure, which resulted in its approval by the Pharmaceutical and Medical Device Agency (PMDA), for use in the treatment of ALS in Japan on 26 June 2015 (3). Mitsubishi Tanabe Pharma Corporation (MTPC) subsequently filed a new drug application for ALS with the US Food and Drug Administration (FDA). On 5 May 2017, the FDA approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS). Edaravone also has orphan drug designation for the treatment of ALS, as granted by the European Commission, since 19 June 2015. In a field where the only disease-modifying agent for treating ALS is riluzole (4,5), which was approved in 1995, the approval of a new disease modifying agent for ALS by the FDA along with other regulatory agencies is welcome news to a population of patients desperate for better therapies grounded in sound scientific principles and good clinical trial design.

As an antioxidant free radical scavenger with potential for use in stroke (6–10) and ALS, edaravone proceeded in development using pre-clinical in vitro and animal modelling. Details of many of the initial in vitro studies and the mechanism of action of edaravone are outlined by Takei et al. in this supplement (11). At the time of its initial development for stroke, free radical scavenging compounds were being explored for their potential in ALS therapeutics (12). Many of these never reached human clinical trials for ALS or, once they did, were either ineffective or never pursued for further development.

It has been suggested that the efficacy of therapeutic compounds in a superoxide dismutase 1 (SOD1)-based mouse model of ALS does not necessarily predict clinical efficacy in humans (13). Which pre-clinical approaches should be used and the degree of efficacy needed to have confidence in predicting success in ALS patient trials is a complex issue and beyond the scope of the current review. Interestingly, edaravone has been studied in three motor neuron disease models. In the SOD1^G93A mouse model, edaravone was given at symptom onset, rather than pre-symptomatically, in an effort to mirror how patients would be treated with edaravone after an ALS diagnosis. Levels of 3-nitrotyrosine (3NT), a marker of free radical formation were elevated in SOD1^G93A mice when compared to controls but, tellingly, there was not a significant reduction of 3NT with varying doses of edaravone. This would suggest that the potential mechanism for any behavioural findings may have been related to an off-target effect of the compound. The multi-target potential for edaravone has been raised previously in the context of its original development for acute ischaemic stroke (reviewed by Lapchak) (14). There was a modest effect on behavioural function and motor neuron sparing in these models but, not unexpectedly given the timing of administration, no effect on survival (15). A study of edaravone in the transgenic SOD1^H46A rat did not show any significant changes in either behaviour or survival (16). A more recent study in the wobbler mouse, a model with some features of a motor neuronopathy, showed that edaravone could attenuate muscle weakness, muscle contracture, denervation muscle atrophy in the forelimb, astrocyte proliferation and motor neuron degeneration of the cervical spinal cord. This study, however, was limited by its short duration of only four weeks (17). All of the aforementioned studies were likely limited by being underpowered in their design or by dosing taking place too late in the course of disease. Therefore, any potential benefits beyond those reported may have been missed.

How, then, should decisions be made to further the development of compounds which show promise preclinically but lack robust findings? This is a difficult question in the context of ALS. However, the international ALS medical community is showing increasing interest in learning lessons from the previous failures of experimental therapies for ALS. Some of these adaptations include new designs for clinical trials that can be completed with fewer patients by utilising futility rules, lead-in, selection of patient sub-groups, and adaptive and sequential designs (18). Furthermore, there has been a push for the development of a variety of biomarkers that may help to measure target engagement, predict disease onset and progression. Consistent with this, the development programme for edaravone has sought to incorporate many of these elements.

With regard to biomarkers, it has been hypothesised that oxidative stress could play a role in ALS based on 3NT levels in both ALS animal models and ALS patients with familial and sporadic disease (19–23). Citing these data, Yoshino et al., in 2006, undertook a phase II study of ALS patients and showed that the infusion of either 30 mg or 60 mg of edaravone resulted in a reduction in CSF 3NT over a six-month period (24). However, this study did not show any dose dependent effect. The study lacked a placebo group and comparisons of 3NT levels could only be made pre- and post-treatment. Consequently, the possibility that 3NT levels in these patients were either variable over time or decreased over the six-month time-frame independent of edaravone administration cannot be excluded.

This preclinical development, occurring over a space of several years, would today be considered a reasonable strategy for investigative ALS therapies with regard to the study of the drug in vitro, in available in vivo models and, with the incorporation of a biomarker, attempting to demonstrate target engagement. Nevertheless, the data from these studies were limited in their ability a priori to predict efficacy in ALS patients but did shed significant light on safety, tolerability, and rationale for further development.

With regard to the clinical phase of development, the designs of several of the trials incorporated a number of the methods outlined above with regard to the inclusion of an observation (lead-in) phase, a relatively short treatment time, and the use of specific (but fairly standard) inclusion criteria to identify a subgroup of patients that could show a meaningful benefit. This initial phase III clinical study of edaravone in ALS patients, published in 2014 by Abe et al. (25), included a 12-week observation period followed by a 24-week treatment period. Inclusion criteria were: age 20–75 years; diagnosis of ‘definite’, ‘probable’ or ‘probable laboratory-supported’ ALS according to the revised Airlie House diagnostic criteria; forced vital capacity (FVC) of at least 70%, disease duration of <3 years, and a change in the ALSFRS-R score during the 12-week observation period of –1 to –4 points. A difference from other international trials was that patients were required to have a Japanese ALS severity classification of 1 or 2 at the start of treatment. This last criterion is noteworthy because it represents a relatively high functioning patient population (1: able to work or perform housework, or 2: independently living but unable to work). Patients in this study received either placebo or edaravone intravenously for the first 14 d of the first cycle and then 10 of the first 14 d of cycles 2–6. There were two-week breaks comprising the remainder of each cycle. The primary endpoint was a change in the ALSFRS-R during this 24-week period. There were no significant concerns with regard to the safety of the compound but this study did not show any efficacy in this Japanese ALS population (25).

Subsequently,, following this initial phase III study (25), an exploratory double blind, parallel-group, placebo-controlled extension study lasting an additional 24-week period was undertaken (26). Patients given edaravone in the first 24-week phase III study (Cycles 1–6) were randomised to edaravone (E-E) or placebo (E-P) in the subsequent 24-week double-blind period (Cycles 7–12). Patients given placebo in phase III were likewise switched to edaravone (P-E). Subsequently, all patients received edaravone for 12 additional weeks (Cycles 13–15). As with the original study by Abe et al. that included the original ALS study population for cycles 1–6, no benefit in any of the outcome measures was observed in this extension study when comparing the E-E group with the E-P group (weeks 7–12). However, the incidence of serious adverse events associated with ALS progression was higher in E-E than in E-P group. These data could suggest that the timing of treatment with edaravone, at a time-point of lesser disability, is important in maintaining a slower progression of disease. However, given the duration of the study, it still may be possible that patients lose any benefit of edaravone and progress at a faster rate later in the disease. The authors note that statistical analyses were performed only between the E-E and E-P group since their baseline characteristics at the beginning of the seventh cycle were similar and allowed for an examination of data through the 12th cycle. However, a further comparative analysis of the P-E group could have shed light on whether edaravone given later during the disease after the sixth cycle, could change disease course.

Perhaps not surprisingly, a smaller exploratory double-blinded study [(MCI-186)ALS 18] of edaravone in patients (13 patients treated with edaravone and 12 with placebo for 24 weeks) with a more severe stage of ALS defined as a Japanese ALS severity classification of 3 (requiring assistance for eating, excretion or ambulation), reported in this supplement (27), did not show that edaravone was efficacious in this ALS population but it did show that side-effects were similar between the edaravone and placebo groups.

In a post-hoc analysis included in this supplement, the investigators sought to understand why edaravone was not effective in the ALS cohorts that made up the full study population of [(MCI-186) ALS 16]. This post-hoc analysis suggested that there were large variations in the clinical courses of the ALS patients, and consequently the range of changes in the ALSFRS-R score was too great to allow for a potential benefit to be observed (28). They subsequently identified two groups in whom a potential benefit could be seen. The first was a sub-population termed the efficacy-expected sub-population (EESP) with pulmonary %FVC of ≥80% of predicted before treatment, and ≥2 points for all item scores in the ALSFRS-R before treatment. The second group also added a diagnosis of ‘definite or ‘probable’ ALS diagnosis and an inclusion of patients according to within two years of initial ALS symptom onset and termed the dpEESP2y (28). Could this post-hoc analysis be meaningful in suggesting that a population with an even more restricted set of clinical features responds to edaravone?

Important to the entire development programme in bringing edaravone to ALS patients was the follow-up study based upon the post-hoc analysis of the original phase III study. In this follow-up study (MCI-186) ALS19, only patients meeting the criteria (dpEESP2y) were included in this study (2). The selection of this subgroup was of particular interest since, while most ALS studies have utilised the ALSFRS-R, %FVC, El Escorial criteria, and disease duration for defining inclusion criteria, this study tended to be more restrictive than the others with these criteria. This reflects a growing trend in ALS studies to try to divide study populations into subgroups that might be more likely to benefit from compounds of interest and to potentially reduce the effects of variability in the underlying time-course of disease progression. Other recent examples of studies with subgroup stratification include a phase I study of an antisense oligonucleotide (ASO) to SOD1 (29) in patients with familial ALS carrying a SOD1 mutation and a larger, phase I, placebo-controlled, single and multiple ascending-dose study to evaluate the safety, tolerability, and pharmacokinetics of BIIB067 (an ASO targeting SOD1) in ALS patients with documented mutations in SOD1 (Clinical trials.gov identifier NCT02623699), which is now underway. Another example is a study of the compound NP001 in ALS (Clinical trials.gov identifier NCT02794857) in which elevated high sensitivity C-reactive protein (hs-CRP) is an inclusion requirement. This was done based upon a previous study suggesting that there was a subgroup of patients responding to NP001 who had elevated systemic inflammation based upon levels of C-reactive protein (30). The study designs of these three trials are illustrative of a recent trend towards clinical subgrouping (edaravone), genetic subgrouping (ASO for familial SOD1 patients), and inclusion criteria based on the presence of specific blood biomarkers (hs-CRP for NP001). In addition to genetic, blood, and fluid biomarkers with the potential to predict subgroups of patients who may be responders, even certain standard clinical ALS subgroups (ALS with FTD, bi-brachial ALS, bulbar-onset ALS, etc.) may be targets for enrolment depending on the particular study.

The primary efficacy endpoint in the MCI-186 ALS 19 pivotal study (2), was the ALSFRS-R score, defined as the change from the baseline to the end of Cycle 6 (six months) (or at discontinuation after the third cycle) after randomisation. The most notable finding was that the mean ALSFRS-R scores from baseline to the end of Cycle 6 (or discontinuation), showed a mean difference between treatment groups in favour of edaravone. Encouragingly, there were also trends in favour of edaravone for the %FVC and Modified Norris Scale and less deterioration for edaravone-treated patients in the ALSAQ-40 (a quality of life scale). However, measures related to strength or ALS disease severity were not altered by the compound (2). The robustness of the results favouring edaravone over placebo was verified in a post-hoc analysis (31) that included additional statistical analyses and the use of the Combined Assessment of Function and Survival (CAFS) – a measure that has been used in more recent ALS clinical trials (32,33).

One of the critical questions is whether the effects of edaravone in ALS will be long-lasting and whether there may be risks involved in long-term use. In an open-label 24--week extension study of MCI-186 ALS 19, there were no long-term side-effects in either the patients who received edaravone for the entire study (E-E) or those who received placebo for cycles 1–6 and edaravone for cycles 7–12 (P-E) . The study was limited by the absence of double-blinding and there was no cohort examining patients who had received placebo for the entire period of the study (P-P group), so the assessment of long-term efficacy (48 weeks) for edaravone was not possible (34).

Challenges

The results of the MCI-186 ALS 19 phase III study suggesting a subset of ALS patients responded to edaravone are exciting for a field that has been looking for novel therapies that could influence disease progression and quality of life for ALS patients.

A number of questions remain regarding edaravone in ALS patients. Perhaps the foremost question is whether ALS patients who do not meet the criteria outlined in the pivotal study (MCI-186 ALS 19) will derive any benefit given that it is now approved for use in Japan and, most recently, the US. The data from the initial phase III study [(MCI-186) ALS 16], would suggest that these patients would not respond to edaravone therapy, at least in the 24-week parameters of this study. It may also be that the window of therapeutic benefit could be limited to a six-month time-frame in the patients who met the criteria and had a high pulmonary FVC and a relatively recent diagnosis. The mechanisms of neuronal injury active during this therapeutic window could also be different from those mechanisms contributing to disability later in the disease. Whether the administration of edaravone over even longer durations (months or years as would be expected with approved clinical use) could result in a slowing of disease remains unanswered. We should also consider the possibility that other ALS subtypes, either clinical subtypes or subtypes defined by other as yet unrecognised biomarkers, could respond over the longer term, but this is only speculation.

It is noteworthy that the dosing of edaravone is marketed to treat acute ischaemic stroke and was originally approved in Japan in 2001. This was based on a dosing of 30 mg intravenously, twice daily, for 14 d and patients with embolic, thrombotic, and lacunar strokes have been found to benefit from its use. However, even the dose, timing of administration after stroke, and duration of treatment have not been standardized (14,35). Although underlying mechanisms of neuronal injury between stroke and ALS may have common ties, the acuity of onset and progression of these disorders are strikingly different. While the data for the studies in ALS stand for themselves, the question as to how the stroke data extrapolate to the ALS data and whether the once daily regimen described in the phase III ALS studies is optimal remains unanswered. This may be particularly relevant for further exploration in ALS to establish if either a simplified regimen with equal efficacy or a modified regimen with even greater efficacy could be obtained.

Is there reason to believe that the success of edaravone in a Japanese population of patients with ALS translate to slowing of disease in other populations? In this issue, Nakamaru et al. and compared pharmacokinetic (PK) profiles between Japanese and Caucasian populations and noted that there were differences in the peripheral volume of distribution between the two populations but, using a simulated population PK model, there were no clinically relevant differences in the PK profiles of edaravone by race, sex, weight or age (36). Nevertheless, there are limitations to this analysis as the authors note that while single and multiple doses of edaravone PK data have been examined in both Japanese and Caucasian healthy patients, there are no PK data for the currently prescribed ALS treatment strategy. Moreover, there are other confounders which include genetic differences among the Japanese and Caucasian populations that may make extrapolation of the efficacy across populations difficult. For example, C9orf72 repeat expansions account for perhaps as much as 8% of all ALS in populations of European ancestry, but are not believed to be represented in Japanese ALS patients (37). Therefore, against the background of the lack of direct data comparing the two populations in the context of ALS, the results proposed suggest that what we might expect regarding PK data among Japanese and Caucasian patients is reassuring but not definitive for extrapolating the potential utility of edaravone across populations.

ALS patients will ask whether edaravone affects survival. The inclination may be to assume that a slowing in the decline of the ALSFRS-R results in prolonged survival but the short duration of these studies and the defined primary endpoints do not directly address this question.

Conclusions

Taken together, the development of edaravone as a treatment for ALS will hopefully continue to fuel optimism in the field of ALS therapeutics. In many ways, the programme has attempted and succeeded in incorporating many of the currently desired benchmarks for clinical research studies. The compound was developed for an anti-oxidant pathway that proved useful in preclinical models of stroke and subsequently in stroke patients. This resulted in a measured effort to examine effects in ALS mouse and rat models leading to its trial in ALS patients. The importance of the MCI-186 ALS 19 study is punctuated by the incorporation of the ALSFRS-R, the most widely applied rating scale in clinical practice and clinical trials as a primary or secondary outcome measure (38). Whereas other ALS trials using the ALSFRS-R have never demonstrated any significant change in the slope of this measure, that edaravone met this measure highlights the validity of its effect.

Perhaps the programme’s greatest achievement was performing the MCI-186 ALS19 study in a subset of ALS patients found to be responders in the post-hoc analysis of the original study which did not show efficacy in the more clinically heterogeneous ALS cohort. Without the follow-up study in this important subset of ALS patients, efficacy would never have been demonstrated for this compound and approval of the drug by the US FDA would not have been realised. It is also noteworthy that the MCI-186 ALS 19 selected an even more clinically defined subgroup of ALS patients as part of the clinical trial design – a concept now being more widely adopted by the ALS community. Interestingly, and potentially excitingly, is the idea that different therapeutic compounds may have efficacy in other ALS subgroups besides those chosen in this development programme. However, identifying those specific subgroups remains a challenge which will perhaps be addressed through emerging works in ‘precision medicine’.

In a field where numerous failures of potential therapeutics have been recorded, a slowing of disease progression using the outcome measures that have been used for most ALS trials, suggests that the effects of edaravone are reliable and functionally meaningful in the ALS population studied. These studies, having been rigorously performed with clinically important findings, should bring a new wave of enthusiasm to the ALS community of patients and caregivers who have tirelessly sought to find better therapeutics for ALS. Hopefully the success of the edaravone development programme is the first of many new therapies for the disease.

Declaration of interest

Scientific Advisory Board of Q Therapeutics, Inc., Scientific Advisory Board, Above and Beyond NB, LLC. Consultant to: Cytokinetics, Inc., Biohaven Pharmaceuticals.

Open access publication of this article was funded by Mitsubishi Tanabe Pharma America, Inc.