As the first FDA-approved drug for ALS (1995), riluzole has been the cornerstone of pharmacological management for decades. Then, Riluzole was approved for the treatment of ALS in most countries (18, 19). Although many other drugs have been studied, it was the only clinically approved treatment for ALS for more than two decades. The chemical structures and key features of riluzole are shown in Figure 1. In ALS, glutamate homeostasis is dysregulated and glutamate-mediated excitotoxicity is regarded as the key mechanism of ALS pathogenesis (20). As a benzothiazole drug, the drug operates on a foundation of neuronal protection, blocking voltage-gated sodium channels to reduce the release of the excitatory neurotransmitter glutamate and increasing glutamate uptake through excitatory amino acid transporter to regulate extracellular glutamate levels (21). This action regulates subsequent intracellular activities post-neurotransmitter binding, and curbs excitotoxicity, thus protecting neurons from damage. Riluzole regulates intracellular Ca²⁺, thereby maintaining calcium homeostasis. In addition, it increases oxidative stress and interferes with integrity of DNA, as well as autophagic and apoptotic pathways (22).

Riluzole is more effective in patients with advanced disease, although it is recommended for patients with all stages of ALS (23, 24). Evidence from clinical trials has validated riluzole’s effectiveness in extending median survival of ALS patients by two to three months and slowing the decline in respiratory capabilities, a significant marker of ALS progression (25). They also indicated that riluzole could positively affect motor functions (25). Real-world investigations from Italy also indicated that riluzole treatment reduced the mortality rate of ALS patients (26). In all the studies, patients demonstrated high adherence to treatment and good drug tolerance. Its use requires vigilance for adverse effects, most notably potential hepatotoxicity, which necessitates regular monitoring of liver function. Despite its long-standing status, the clinical benefits of riluzole are modest. It extends median survival by only approximately 2 to 3 months, a benefit that many patients and clinicians consider limited in the face of a rapidly progressive disease (27). Furthermore, real-world evidence regarding its effectiveness remains mixed. Some observational studies have reported no significant improvement in survival or functional decline, highlighting the discrepancy that can exist between controlled clinical trials and broader clinical practice (28). Safety monitoring is also required, as post-marketing surveillance indicates a need for vigilance regarding adverse events such as interstitial lung disease, hepatic dysfunction, and pancreatitis (5). However, there are also surveys indicating that riluzole neither improved survival nor slowed functional decline in ALS patients (28). These contradictory clinical investigation results indicate the limited efficacy of the drug. The evidence is still insufficient to draw any definite conclusion and more extensive research is needed.

Edaravone, approved in Japan (2015) and the US (2017), represents another major pharmacological option, particularly indicated for early-stage ALS (23). Its chemical structures and key features are shown in Figure 1. The full extent of its therapeutic effects in ALS is still being under comprehensive exploration. Oxidative stress is considered to be involved in the pathology of ALS. Edaravone exhibits strong biological activities including inhibition of oxidative stress and scavenging free radicals (29). Its antioxidant mechanism is central to its efficacy, skillfully countering the pernicious reactive oxygen species (ROS) that initiate lipid peroxidation, although its specific mechanism of action is still unknown (30). Studies have shown that edaravone reduces the accumulation of hydrogen peroxide (H₂O₂) through upregulation of Peroxiredoxin-2 (31), and can also trap hydroxyl radicals (^{. OH}) and peroxynitrite anions (ONOO⁻) in its anionic form (30). Furthermore, the drug’s impact is notably robust in the context of cerebral ischemia and reperfusion, adeptly mitigating oxidative stress, brain edema, and the resultant tissue damage by inhibiting NADPH oxidase 2 (NOX2) (32).

A 2.5-year retrospective study from India suggests that intravenous edaravone treatment has no beneficial effect on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS) score and does not improve survival rate (33). Another observational study from India shows that edaravone infusion does not stop or significantly slow progression of ALS from baseline but is safe (34). On the contrary, clinical trials from the United States have shown that edaravone oral suspension can significantly prolong survival time and reduce the decline of physical functions (35). These recent clinical investigation results all suggest that edaravone has limited efficacy in the treatment of ALS. In addition, the application of edaravone has been expanded to include acute ischemic stroke, with a Phase III clinical trial underscoring the enhanced efficacy of edaravone when combined with dexborneol, suggesting the merits of this combined approach (36). The approval of edaravone for both ALS and stroke therapy signifies a significant leap forward in neuroprotective strategies. Considering its capacity to target oxidative stress, a pervasive factor in numerous neurological disorders, edaravone is poised to extend its relevance beyond its current indications. Upcoming studies may reveal additional therapeutic potential for edaravone, including its synergistic interactions with other compounds or its utility in addressing a wider spectrum of neurological diseases. With ongoing clinical investigations, edaravone holds the promise of refining patient outcomes and enriching the array of options within the neurological treatment domain. Important safety considerations include the risk of hypersensitivity reactions and the need for renal function monitoring during treatment. The efficacy evidence for edaravone is primarily derived from clinical trials in East Asian populations, and its benefits have been less consistently replicated in Western studies and real-world settings outside of Japan. This discrepancy may be attributed to disease heterogeneity, differences in patient enrollment criteria (e.g., disease stage and progression rate), or genetic factors (37). A real-world study from India suggested that edaravone infusion did not significantly alter disease progression (34). While generally safe, post-marketing data analysis indicates that adverse events related to edaravone, though mostly non-severe, do occur and necessitate clinical awareness (38, 39). These factors collectively suggest that edaravone’s therapeutic effect may be most pronounced in a specific subset of ALS patients, and its global applicability requires further careful evaluation.

AMX0035 (sodium phenylbutyrate and taurursodiol) received conditional approval in 2022 based on early-phase data, representing a novel dual-pathway targeting approach. The safety and tolerability of AMX0035 had been previously confirmed in small PALS trials. The phase 2 CENTAUR study and its open-label extension demonstrated the safety and efficacy of AMX0035 in PALS (7). AMX0035 had shown significant slowing of disease progression and prolonged survival (40). It is worth noting that Amylyx Pharmaceuticals announced the results of the phase 3 PHOENIX trial of AMX0035 for the treatment of ALS in 2024. The primary endpoint or secondary endpoints did not reach statistical significance as measured by change from baseline in the Revised ALSFRS (ALSFRS-R) or ALSAQ-40 and SVC, despite with good tolerance and safety. Survival data will continue to be collected. The journey of AMX0035 underscores the critical challenge of replicating early positive signals in larger, confirmatory trials. While the phase 2 CENTAUR trial showed a slowing of functional decline, the subsequent phase 3 PHOENIX trial failed to meet its primary or secondary efficacy endpoints, leading to the drug’s voluntary withdrawal from the market (7). Several hypotheses may explain this discrepancy. The PHOENIX trial had a longer placebo-controlled period (48 vs. 24 weeks) and a more geographically diverse population, which may have introduced greater clinical variability (41). Differences in baseline patient characteristics, including a lower concurrent use of other ALS therapies in PHOENIX compared to CENTAUR, might also have influenced outcomes. An expert commentary suggested that the positive result in the smaller CENTAUR trial could have been a false positive, or that the treatment effect is too small to be reliably detected without highly homogeneous patient groups (42). This case highlights the risks of accelerated approvals based on single, modest-sized trials and the imperative for robust phase 3 validation. Amylyx has announced that it has started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for AMX0035 based on topline results from the Phase 3 PHOENIX trial. The therapy was generally well-tolerated, with gastrointestinal events such as diarrhea and abdominal pain being the most frequently reported adverse effects. The limited efficacy of the currently approved clinical drugs highlights the need for the study and development of new drugs.

Tofersen, crafted by Biogen as an innovative antisense oligonucleotide therapy, has a specific indication for adults with ALS who have a mutation in the SOD1 gene. This precision medicine disarms the disease at the genetic level by hybridizing with SOD1 mRNA, orchestrating its degradation and consequently snuffing out the production of the detrimental SOD1 protein (8, 43, 44). Intrathecal administration ensures that tofersen targets motor neurons with pinpoint accuracy through cerebrospinal fluid, effectively diminishing cerebrospinal levels of SOD1 protein and plasma levels of neurofilament light chains—biomarkers that signal the regression of neuronal damage (43).

Although the VALOR trial did not meet its primary milestone, tofersen’s ability to significantly reduce these biomarkers was not overlooked, earning it an expedited FDA approval on April, 2023 (9). Marking its place as the fourth ALS treatment and pioneering the way as the inaugural gene therapy to gain accelerated approval anchored in biomarker evidence, tofersen is a landmark in the field of gene therapy for ALS (45). It extends a beacon of hope and a novel therapeutic avenue to improve the medical prognosis and quality of life for people living with SOD1 mutation-associated ALS. Recent analyses highlight that tofersen not only validates the genetic approach but also enhances therapeutic opportunities by potentially altering the disease course when initiated early, though accessibility and long-term management strategies remain areas for development (46). Serious adverse events associated with its intrathecal administration include myelitis/radiculitis and elevations in intracranial pressure, requiring careful clinical monitoring. The approval of tofersen represents a landmark in precision medicine for ALS but also introduces a nuanced paradigm for evaluating efficacy. Crucially, the pivotal VALOR phase 3 trial did not meet its primary clinical endpoint (change in ALSFRS-R score at 28 weeks) (44). Its accelerated approval was primarily based on a compelling reduction in plasma neurofilament light chain (NfL), a biomarker of neuronal damage, which decreased by approximately 60% in the tofersen group compared to 20% in the placebo group (44). This dissociation underscores the principle that biomarker improvement does not equate to immediate, measurable clinical benefit, suggesting a potential delay between biological effect and functional stabilization (47). The ongoing ATLAS study in presymptomatic SOD1 carriers may provide further insights into whether early intervention can delay clinical onset. Thus, tofersen illustrates both the promise of targeted genetic therapy and the current reality that its most significant impact may be on disease biology, with clinical benefits requiring longer timeframes to manifest or being more modest than initially hoped.

Nuedexta, a synergistic blend of dextromethorphan hydrobromide and quinidine sulfate, has received FDA approval for the treatment of pseudobulbar affect (PBA) in ALS patients in 2010 (48). The formulation’s efficacy is based on dextromethorphan’s effect on neurotransmission, which can mitigate excitotoxic effects, coupled with quinidine’s ability to enhance dextromethorphan’s cerebral presence by inhibiting efflux transporter activity (49). This pharmacological tandem enhances Nuedexta’s ability to stabilise the neural messengers that regulate emotional responses, thereby alleviating the distress of PBA.

Expanding its therapeutic horizons, Nuedexta is being investigated for its benefits in ALS, where it may provide neuroprotection by targeting the sigma-1 receptor and limiting glutamate-induced excitotoxicity (50). Preliminary clinical evidence suggests that Nuedexta may support bulbar functions critical to speech, swallowing and breathing in ALS, while managing a spectrum of manageable side effects (51). As the understanding of Nuedexta, it may emerge as a multi-faceted therapeutic contender, able to address a range of emotional and motor challenges across the spectrum of neurodegenerative diseases.

Preclinical studies in animal models have established the foundational rationale for this approach. Research utilizing models such as the SOD1 G93A transgenic mouse has demonstrated that stem cell transplantation can attenuate neuroinflammation and provide trophic support. For instance, MSC transplantation in these models has been shown to modulate the neuroinflammatory milieu by suppressing the activation of detrimental immune cells (58). Furthermore, stem cells offer a platform for delivering neurotrophic factors; for example, neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (GDNF) have been explored in preclinical settings (59). These investigations suggest that benefits may arise not only from potential cell replacement but also through powerful paracrine effects. However, challenges such as the long-term survival and integration of transplanted cells within the hostile ALS microenvironment remain significant hurdles in preclinical models (60, 61). The combination of biomaterials and stem cells is also being investigated as a new approach in preclinical research (62). Beyond direct therapy, stem cells are deployed to model ALS in vitro, providing insights into disease mechanisms and revealing new therapeutic targets (63).

Translation to human trials has progressed through several phases, with early-phase studies primarily assessing safety and feasibility. A phase 1/2a trial demonstrated that the transplantation of human neural progenitor cells secreting GDNF (CNS10-NPC-GDNF) into the spinal cord was feasible and safe over 42 months, with no negative effects on motor function (64). Another pivotal phase 3 trial evaluated MSCs induced to secrete neurotrophic factors (MSC-NTF, NurOwn). While the study reported positive effects on cerebrospinal fluid biomarkers of neuroinflammation and neurodegeneration, it did not meet its primary clinical efficacy endpoint, highlighting the difficulty of translating biological signals into measurable clinical benefits in a heterogeneous patient population (65). These clinical trials are diligently assessing the safety, feasibility, and efficacy of various stem cell types and transplantation strategies (64, 65). The common challenges faced in clinical translation include immune rejection, the variability in patient responses, and the need for standardized cell products and delivery protocols. The decisive impact on disease trajectory and survival rates remains under investigation, underscoring the need for further rigorously designed clinical studies.