AMYOTROPHIC LATERAL SCLEROSIS (ALS) is a devastating progressive motor neuron disease. The majority of ALS is sporadic with uncertain pathophysiology, which limits effective treatment approaches. ALS poses diagnostic challenges because of various clinical presentations.
Diagnosis can typically be delayed 10 to 16 months from symptom onset1 because of misdiagnosis or delay in getting to neurologists or neuromuscular specialists. With an anticipated life expectancy of 3 years from time of symptom onset,2 an effective treatment strategy is essential. The recent FDA approval of sodium phenylbutyrate/taurursodiol (PB-TURSO) (Relyvrio; Amylyx Pharmaceuticals) now gives clinicians 3 medication options for ALS treatment in the United States.
The first treatment approved for ALS was riluzole (Rilutek; Sanofi) in 1995. Riluzole’s mechanism of action is to block glutamate release, a theory as to why motor neurons die in ALS.3 Since then, riluzole has been approved in oral suspension (Tiglutik, in 2018) and dissolvable oral film formulations (Exservan, in 2019). Although it was the first approved ALS medication, it was a modest step in the right direction, delaying symptom progression and death by just 3 months. The ongoing research for another treatment continued for decades before the FDA approved a new therapy.
Edaravone (Radicava; Mitsubishi Tanabe Pharma Corporation) was approved by the FDA in May 2017, more than 2 decades since the release of riluzole. It has been proposed that oxidative stress may contribute to the pathophysiology of ALS, and edaravone works as an antioxidant, although its specific mechanism is unknown.4 Edaravone first came in the form of an intravenous (IV) infusion and an oral suspension was approved in May 2022. Many patients deferred treatment with the IV formulation due to burden of infusions (daily for 10-14 days per 28-day cycle).
Efficacy data of edaravone IV (Radicava IV) in a double-blind phase 3 study (NCT00330681) did not show significance vs placebo; however, a post hoc analysis of the study suggested a narrowed patient population of milder symptoms (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R] score of at least 2 on all 12 items, and forced vital capacity > 80) might benefit. The following assessment of the therapy in the phase 3 pivotal trial (NCT01492686) demonstrated that treatment with edaravone IV slowed the loss of physical function by 33%—or a 2.49-point difference (P = .0013)—compared with placebo, as measured by the ALSFRS-R.1,2,5 Subsequent studies on survival have shown variable results. A retrospective trial in the United States showed prolonged survival of 6 months (29.5 months with edaravone vs 23.5 months without; P = .005).6 Two studies in Europe did not show a significant benefit in survival.7 Edaravone is not approved for the treatment of ALS in Europe.
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TABLE. Agents in Development for Amyotrophic Lateral Sclerosis
In September 2022, the FDA announced the aforementioned approval of PB-TURSO under the brand name Relyvrio. PB has been known to act as a chemical chaperone to prevent protein misfolding whereas TURSO’s regulatory influence on apoptosis pathways had been studied.8,9 The phase 2 CENTAUR trial (NCT03127514), showed a reduction of ALSFRS-R score of −1.24 points/mo with the active drug and −1.66 points/mo with placebo (P = .03).10 It also showed increased survival by 5 to 6 months.
PB-TURSO’s approval was controversial. It underwent an FDA priority review because of the aggressive nature of ALS. In March 2022, the Peripheral and Central Nervous System Drug Advisory Committee (PCNSDAC) had ruled 6 to 4 against recommending the approval of PB-TURSO.11 Several issues were brought to the committee’s attention, including flaws in study design and data interpretation. Randomization was not truly random because the first 18 patients were assigned to the treatment group. This was because placebos had not shipped by the time of the study’s start date. Some participants had stopped taking PB-TURSO but remained in the survivor analysis. Additional post hoc analysis was provided and, in September 2022, the same committee voted 7 to 2 in favor of PB-TURSO.12 Thousands of public comments pleading for the approval may have swayed some committee members who were on the fence with the first vote.
The open label extension (OLE) of CENTAUR provided additional survival data suggesting that individuals on treatment had roughly an additional 10 months of survivability compared with placebo.13 We previously mentioned that a number of participants had stopped treatment but remained in survival data and this was also the case with the OLE study. The phase 3 PHOENIX trial (NCT05021536) is ongoing with results expected in 2024.14
Tofersen and Antisense Therapeutics in ALS
Data from the phase 3 VALOR study (NCT02623699), and its extension that highlighted tofersen (Biogen) as a potential treatment for amyotrophic lateral sclerosis (ALS) were presented at the Annual Northeast ALS Consortium Meeting, held November 1 to 3, 2022, in Clearwater Beach, Florida. Investigator Timothy Miller, MD, PhD, the codirector of the ALS Center at Washington University School of Medicine in St Louis, Missouri, spoke to NeurologyLive® about tofersen, the improved understanding of SOD1 ALS and antisense therapies, and how the agent might fit into the treatment landscape.
Q: If it were to be approved, what role could tofersen play in ALS treatment?
TIMOTHY MILLER, MD, PHD: Tofersen is going way up upstream, targeting the genetic mutation in SOD1 [ALS], abnormal DNA, abnormal RNA, and tofersen is removing the RNA, or gene product. It’s going way upstream in the setting of ALS. The other approved therapies aren’t, as far as we know, targeting things at that level. They’re targeting things that are further downstream. I would see no reason why someone couldn't be or wouldn’t be on tofersen and other approved therapies for ALS. I don’t see any contraindications to that at the moment. I would say they would work in conjunction with [tofersen]. The other point to make is people treated with tofersen did better, and I think we’re doing well, but there’s still room for improvement. There’s not a reason not to consider all the potential therapies available to anybody with ALS.
Q: Are there any specific advantages to tofersen?
The main advantage to this type of therapy is that it’s targeting the underlying cause of the disease. I should be clear, we don't know enough about ALS to know whether other approved therapies are also targeting upstream, the underlying causes of disease. We just don’t know yet. But many of us assume that a drug like tofersen for SOD1 ALS, is targeting SOD1. That’s the cause of the disease. We’re very upstream, removing the gene product that most of us believe is causing ALS and in people with this genetic disorder.
Q: Have there been any discussions about conducting a longer trial of tofersen’s effect?
I think all considerations are on the table right now for how tofersen may be used. I think we’re gaining experience for longer treatment, and so that would be one consideration. I think another interesting point is: Could we treat early with a drug like tofersen? I’m talking very, very early, and there is an ongoing trial—ATLAS [NCT04856982]—sponsored by Biogen. Michael Benatar, DPhil, MBChB, MS, is the academic lead. The idea is to follow people presymptomatically who have a known mutation. We’re going to follow that group, monitor neurofilament levels, and use the neurofilament level or symptoms that develop as a reason to convert or think about treating that person with tofersen. That’s an interesting new study. I shouldn’t say new, it’s an ongoing study for people who are asymptomatic with SOD1 mutations, and I think we’ll learn a lot from that study about hopefully preventing the occurrence of symptomatic ALS. We’re catching it in its very, very earliest phase.
During the meeting with PCNSDAC in September 2022, Amylyx had stated its willingness to pull the medication from the market if there was a lack of confirmatory outcomes from PHOENIX.
More than 50 drugs are under investigation for the treatment of ALS. Some treatments are already available in the market for other indications whereas others are novel interventions (TABLE).
Dextromethorphan/quinidine (Nuedexta; Avanir Pharmaceuticals) was approved in 2010 for the treatment of pseudobulbar affect in patients with ALS. Following anecdotal reports of improved bulbar function, a phase 1/2 trial (NCT03883581) was recently completed evaluating its effectiveness in treatment of bulbar ALS,15 but results have yet to be released.
High-dose mecobalamin was first evaluated in a phase 2/3 clinical trial (NCT00445172) in 2015, showing a decrease in ALSFRS-S scores but not significant results.16 The trial suggested that a higher dose (50 mg) and earlier disease population showed more benefit. A new phase 3 trial, JETALS (NCT03548311), was thus started and recently completed, showing a 1.97 ALSFRS-S decrease at 16 weeks (−2.66 vs −4.63; 95% CI, 0.44-3.50; P = .01).17 Eisai has announced plans to submit for approval.18
The HEALEY ALS Platform trial (NCT04297683) has increased the chance of finding an effective treatment. Among the candidates, CNM-Au8 is a gold nanocrystal suspension. Recently updated phase 2 RESCUE-ALS study (NCT04098406) data showed a 70% decreased risk of death compared with placebo (P = .0143). At week 36, CNM-Au8 demonstrated a 6-point decrease in ALSFRS-R score (P = .35).19 Additionally, the trials of verdiperstat, an oral myeloperoxidase inhibitor, and pridopidine, a σ-1 receptor agonist, have ended enrollment and results are expected in the near future.20
It is an exciting time in the world of ALS as we see more interventions approved and many under investigation for this rare disease. Although the currently approved medications are prolonging life by only a few months, that is valuable time for the patients and their families being affected by this devastating disease. It will take the collaborative efforts of the scientific community and the general ALS community to continue to propel us in the right direction.
Hopefully, with the advent of better treatments, we will have the decision of which are more cost-effective with improved clinical results. With 3 treatments of different mechanisms and benefits that are additive, we are now better able to treat ALS than ever.
Richards D, Morren JA, Pioro EP. Time to diagnosis and factors affecting diagnostic delay in amyotrophic lateral sclerosis. J Neurol Sci. 2020;417:117054. doi:10.1016/j.jns.2020.117054
Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7(11):639-649. doi:10.1038/nrneurol.2011.153
Martin D, Thompson MA, Nadler JV. The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1. Eur J Pharmacol. 1993;250(3):473-476. doi:10.1016/0014-2999(93)90037-i
Watanabe K, Tanaka M, Yuki S, Hirai M, Yamamoto Y. How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr. 2018;62(1):20-38. doi:10.3164/jcbn.17-62
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;16(7):505-512. doi:10.1016/S1474-4422(17)30115-1
Brooks BR, Berry JD, Ciepielewska M, et al. Intravenous edaravone treatment in ALS and survival: an exploratory, retrospective, administrative claims analysis. EClinicalMedicine. 2022;52:101590. doi:10.1016/j.eclinm.2022.101590
Lunetta C, Moglia C, Lizio A, et al; EDARAVALS Study Group. The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis. J Neurol. 2020;267(11):3258-3267. doi:10.1007/s00415-020-09993-z
Yam GHF, Gaplovska-Kysela K, Zuber C, Roth J. Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilin to rescue cells from endoplasmic reticulum stress and apoptosis. Invest Opthalmol Vis Sci. 2007;48(4):1683-1690. doi:10.1167/iovs.06-0943
Elia AE, Lalli S, Monsurrò MR, et al. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2016;23(1):45-52. doi:10.1111/ene.12664
Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. N Engl J Med. 2020;383(10):919-930. doi:10.1056/NEJMoa1916945
March 30, 2022 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. YouTube. Accessed January 17, 2023. https://www.youtube.com/watch?v=AVVZMMvDOUg
September 7, 2022 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. YouTube. Accessed January 17, 2023. https://www.youtube.com/watch?v=6PMOyqd6WfA
Paganoni S, Watkins C, Cawson M, et al. Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: evaluating the impact of treatment crossover on outcomes. Muscle Nerve. 2022;66(2):136-141. doi:10.1002/mus.27569
Amylyx Pharmaceuticals announces FDA advisory committee supports approval of AMX0035 for the treatment of ALS. News release. Amylyx Pharmaceuticals. September 7, 2022. Accessed January 14, 2023. https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-fda-advisory-committee-supports-approval-of-amx0035-for-the-treatment-of-als
Smith R, Pioro E, Myers K, et al. Enhanced bulbar function in amyotrophic lateral sclerosis: the Nuedexta treatment trial. Neurotherapeutics. 2017;14(3):762-772. doi:10.1007/s13311-016-0508-5
Kaji R, Imai T, Iwasaki Y, et al. Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study. J Neurol Neurosurg Psychiatry. 2019;90(4):451-457. doi:10.1136/jnnp-2018-319294
Oki R, Izumi Y, Fujita K, et al; Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators. Efficacy and safety of ultrahigh-dose methylcobalamin in early-stage amyotrophic lateral sclerosis: a randomized clinical trial. JAMA Neurol. 2022;79(6):575-583. doi:10.1001/jamaneurol.2022.0901
Eisai initiates preparation for new drug application, based on the results of an investigator-initiated clinical trial of ultrahigh-dose mecobalamin for amyotrophic lateral sclerosis in Japan. News release. Eisai. May 10, 2022. Accessed January 14, 2023. https://www.eisai.com/news/2022/news202231.html
Meglio M. CNM-Au8 shows continued decreases in ALS mortality, updated open-label findings show. NeurologyLive ®. July 21, 2022. Accessed January 14, 2023. https://www.neurologylive.com/view/cnm-au8-continued-decreases-als-mortality-updat ed-open-label-findings
Study drugs in the HEALEY ALS platform trial. Massachusetts General Hospital. Accessed January 14, 2023. https://www.massgeneral.org/neurology/als/research/first-platform-trial-treatments