Witzel S, Maier A, Steinbach R, Grosskreutz J, Koch JC, Sarikidi A, Petri S, Günther R, Wolf J, Hermann A, Prudlo J, Cordts I, Lingor P, Löscher WN, Kohl Z, Hagenacker T, Ruckes C, Koch B, Spittel S, Günther K, Michels S, Dorst J, Meyer T, Ludolph AC, German Motor Neuron Disease Network (MND-NET). Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022 Feb 1;79(2):121-130. PubMed.
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Duke University
Drug development in ALS is not easy.
From a science standpoint, we don’t know what causes 90 percent of the cases. We suspect there may be subsets of ALS with different pathologies driving progression in different patients at different times, but we have no good way to identify these. We do not typically have pharmacodynamic biomarkers telling us we are hitting our targets with the doses and routes of administration we chose. The outcome measures we do have are clinical, things like disability questionnaires, breathing volumes, muscle strength testing. These are noisy and slow to change. There is disagreement over what a clinically meaningful change on these measures looks like. ALS trials enroll slowly for a variety of reasons, and so it can be years between the first patient enrolled and the availability of results. Given all this, it is hardly surprising that replication (one of the fundamental principles of good science) is rare in ALS trials. Either no confirmatory trial is done, as in the case of Radicava, aka edaravone, or the follow-up trial fails to replicate the previous “positive” result, as in the case with lithium, dexpramipexole, and NP001.
From a humanitarian standpoint, ALS is still the worst disease I have come across in all my years in medicine. One of my patients described it as follows: “You put me in a box with this diagnosis, and every day it gets smaller on all sides, further restricting what I can do. Eventually it will get so small and tight that it will crush me to death.” Given this, it is easy to see why people living with ALS (PALS) are frustrated, sometimes angry, that after more than 100 years of ALS research we do not have better treatments. They have channeled these emotions into impressive advocacy efforts, and through these have changed laws. I suspect these advocacy efforts also played a major role in the 2017 FDA approval of Radicava, which occurred after just one small, short-duration trial showed a marginal signal on a single clinical outcome measure.
So how can we reconcile the scientific need for replication in ALS trials with the humanitarian need for more treatment options? I see three possibilities. First, we can approve new ALS drugs with just one positive trial and call for “real world” follow-up studies as we have here with Radicava. The problem is, even a well-designed “real world” study, like this one by Witzel and colleagues, cannot provide the same degree of proof as a trial would. I personally doubt Radicava’s efficacy even more after this real-world study, but without another randomized, double-blind, placebo-controlled trial, I will never truly know whether it works or in whom. The 2017 FDA approval removed incentive for the company that owns it to ever sponsor another trial.
Second, we could use “conditional approvals” for ALS drugs, as was recently done with aducanumab. This way we could get a drug with preliminary evidence of safety and efficacy into the hands of those who need it, while at the same time requiring a confirmatory trial. A question I have about this option is, if the drug is widely available, how well will that second trial enroll?
Finally, we could require replication before any kind of approval, but, once safety is established in the first trial, utilize large, expanded-access programs to make the drug available to those who cannot qualify for the trial. I personally like this last option best. There certainly are challenges to creating expanded-access programs at the level of the sponsor and the treating physician, but new financial resources, such as Act for ALS, and educational resources, such as those being assembled on the NEALS Website, should offer solutions.
Barrow Neurological Institute
In 2017, edaravone became the second potentially disease-modifying therapy for ALS in the United States. Approval was granted on the basis of two studies performed in Asia (Abe et al., 2014; Writing Group; Edaravone (MCI-186) ALS 19 Study Group, 2017). The first study employed fairly standard inclusion criteria, with a treatment duration of 24 weeks. Though trends toward efficacy were noted, no statistically significant signal was found. Subgroup analysis suggested that the numerically greatest signal was seen in participants with short disease duration, ALS that was diffuse within the motor system, and who showed evidence of decline prior to treatment. A second study selected patients to maximize these attributes and showed statistically significant slowing of progression on the ALSFRS-R and ALSAQ-40, and a nonsignificant trend toward reduction in rate of decline in vital capacity.
There have been no subsequent placebo-controlled trials, though a trial is in progress comparing two dose levels of edaravone. A study evaluating the impact of edaravone on multiple pharmacodynamic markers is also underway (Berry et al., 2021). The results of both these studies will provide evidence to either buttress support for the use of edaravone or raise questions about its use. Further data has been gleaned from post-hoc analyses of the original randomized studies, which, not surprisingly, show efficacy signals (Brooks et al., 2021; Brooks et al., 2022; Shefner et al., 2020). In addition, there have been multiple efforts to investigate “real-world efficacy” of edaravone, either through single-center studies or descriptions of aggregated data (Houzen et al., 2021; Ismail et al., 2020; Lunetta et al., 2020; Ohta et al., 2020; Park et al., 2020; Vu et al., 2020). While some of these studies suggest benefit of edaravone treatment, others show no impact.
This German study in JAMA Neurology uses aggregated data from patients treated with edaravone, and compares them to a propensity score matched cohort (Witzel et al., 2022). No benefit of treatment with edaravone was noted. While this is a very carefully and well-done study, it should be placed in the context of other open-label evaluations. In Germany, edaravone is available under “special access conditions,” which are not described in the paper but could create a situation of inequality between treated and untreated patients. Propensity matching techniques are effective at matching explicit criteria, but cannot match other factors not included in the algorithm.
A vigorous debate still rages about whether edaravone was approved with sufficient clinical trial data; however, it is unlikely unanimity can be reached regarding exactly what would be sufficient. Older ALS clinician-investigators may recall the controversy surrounding the approval of riluzole even after two large Phase 3 trials (Bensimon et al., 1994; Lacomblez et al., 1996). Real-world experiences are important, but cannot provide the same level of information as well-designed clinical trials. In my view, the current study does not provide evidence to change prescribing patterns of edaravone, but it should provoke further studies to more completely evaluate its use.
References:
Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, Hamada C, Kondo K, Yoneoka T, Akimoto M, Yoshino H, Edaravone ALS Study Group. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):610-7. Epub 2014 Oct 6 PubMed.
Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3;330(9):585-91. PubMed.
Berry J, Brooks B, Genge A, Heiman-Patterson T, Appel S, Benatar M, Bowser R, Cudkowicz M, Gooch C, Shefner J, Westra J, Agnese W, Merrill C, Nelson S, Apple S. Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design. Neurol Clin Pract. 2021 Aug;11(4):e472-e479. PubMed.
Brooks BR, Pioro EP, Beaulieu D, Taylor AA, Schactman M, Keymer M, Agnese W, Perdrizet J, Apple S, Ennist DL. Evidence for generalizability of edaravone efficacy using a novel machine learning risk-based subgroup analysis tool. Amyotroph Lateral Scler Frontotemporal Degener. 2021 Jul 10;:1-9. PubMed.
Brooks BR, Pioro EP, Katz J, Takahashi F, Takei K, Zhang J, Apple S. Slowing the loss of physical function in amyotrophic lateral sclerosis with edaravone: Post hoc analysis of ALSFRS-R item scores in pivotal study MCI186-19. Muscle Nerve. 2022 Feb;65(2):180-186. Epub 2021 Dec 10 PubMed.
Writing Group, Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017 Jul;16(7):505-512. Epub 2017 May 15 PubMed.
Houzen H, Kano T, Horiuchi K, Wakita M, Nagai A, Yabe I. Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan. Pharmaceuticals (Basel). 2021 Jul 21;14(8) PubMed.
Ismail II, Massoud F, Kamel WA, Al-Hashel JY. Evaluation of clinical outcome and safety profile of edaravone in treatment of amyotrophic lateral sclerosis: a 72-week single-center experience. Acta Neurol Belg. 2020 Jul 10; PubMed.
Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996 May 25;347(9013):1425-31. PubMed.
Lunetta C, Moglia C, Lizio A, Caponnetto C, Dubbioso R, Giannini F, Matà S, Mazzini L, Sabatelli M, Siciliano G, Simone IL, Sorarù G, Toriello A, Trojsi F, Vedovello M, D'Ovidio F, Filippi M, Calvo A, and EDARAVALS Study Group. The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis. J Neurol. 2020 Nov;267(11):3258-3267. Epub 2020 Jun 17 PubMed.
Ohta Y, Yamashita T, Nomura E, Hishikawa N, Ikegami K, Osakada Y, Matsumoto N, Kawahara Y, Yunoki T, Takahashi Y, Takamiya M, Tadokoro K, Sasaki R, Nakano Y, Tsunoda K, Sato K, Omote Y, Takemoto M, Abe K. Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients. J Neurol Sci. 2020 Aug 15;415:116906. Epub 2020 May 15 PubMed.
Park JM, Kim SY, Park D, Park JS. Effect of edaravone therapy in Korean amyotrophic lateral sclerosis (ALS) patients. Neurol Sci. 2020 Jan;41(1):119-123. Epub 2019 Aug 30 PubMed.
Shefner J, Heiman-Patterson T, Pioro EP, Wiedau-Pazos M, Liu S, Zhang J, Agnese W, Apple S. Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19). Muscle Nerve. 2020 Feb;61(2):218-221. Epub 2019 Nov 11 PubMed.
Vu M, Tortorice K, Zacher J, Dong D, Hur K, Zhang R, Good CB, Glassman PA, Cunningham FE. Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System. JAMA Netw Open. 2020 Oct 1;3(10):e2014645. PubMed.
Witzel S, Maier A, Steinbach R, Grosskreutz J, Koch JC, Sarikidi A, Petri S, Günther R, Wolf J, Hermann A, Prudlo J, Cordts I, Lingor P, Löscher WN, Kohl Z, Hagenacker T, Ruckes C, Koch B, Spittel S, Günther K, Michels S, Dorst J, Meyer T, Ludolph AC, German Motor Neuron Disease Network (MND-NET). Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022 Feb 1;79(2):121-130. PubMed.
Massachusetts General Hospital, HMS
Edaravone was approved in several countries based on a pivotal, positive placebo-controlled trial in people with early ALS. This was a small trial and there remain questions about the drug, including whether it is effective in all stages of the illness or only in the subset of people similar to those enrolled in the trial. Also, there is a question of whether daily dosing would be more effective. Lastly, questions have been raised about whether the participants in the placebo arm of the pivotal trial progressed faster than expected. The ALS community, through meetings with the FDA, made clear that they were willing to assume more risk and less certainty about treatments prior to approval while additional studies were planned. This approach is similar to regulatory pathways in some oncologic fields.
There is a regulatory requirement for an additional study at higher dosages. This trial is underway with an oral formulation administered every day.
Therefore, the community will have additional information from a placebo-controlled additional trial of edaravone, albeit a different formulation (oral) and dosing (daily).
This paper is an important contribution to knowledge about edaravone. However, it was not a randomized, controlled trial, and the authors point out the challenges to interpretation of results in that setting.
We have heard from people with ALS that every point difference in the ALSFRS-R is important—retaining function for longer is clinically meaningful to those with the illness. I am confident that eventually we will find drugs that have more and more positive impact on slowing and ultimately stopping ALS. We need, however, not to throw away new therapies too quickly, even if their effects might be incremental. One day we will be able to do that because we will have even better drugs.
Continued discussion on accelerated approval pathways and how, as a field, we can continue to move faster to approvals of effective treatments, while also allowing post-approval studies, is very important. This Witzel paper is one important example of how to gather real-world data to inform people with ALS and clinicians. Comparing these types of studies to the randomized, placebo-controlled results is important so we can keep improving how therapies are tested and determined effective or not.
I am not convinced, though, that this report means edaravone doesn’t work. I would like to see results of the ongoing edaravone oral-dosing study for final conclusions. In the meantime, the decision whether to start edaravone or not is important for people to make with their neurologists after reviewing the data on efficacy and safety.
We can learn a lot as a field from drug development in oncology. The ongoing study of oral edaravone and the Phoenix study for AMX035 are two approaches to continue to gather additional critical data on new treatments. We all want to be sure drugs are safe and effective. The discussion in the community now is more around timing of these repeat studies. The community might not entirely agree on this but must engage in these discussions together to move the field forward.
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