Amyotrophic Lateral Sclerosis Drug Research Articles

Assessing the efficacy of amyotrophic lateral sclerosis drugs in slowing disease progression: A literature review.

Amyotrophic lateral sclerosis (ALS) is a fatal and intricate neurodegenerative disease that impacts upper and lower motor neurons within the central nervous system, leading to their progressive destruction. Despite extensive research, the pathogenesis of this multifaceted disease remains elusive. The United States Food and Drug Administration (FDA) has granted approval for seven medications designed to address ALS and mitigate its associated symptoms. These FDA-sanctioned treatments are Qalsody, Relyvrio, Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta. In this review, the effects of these seven drugs on ALS based on their mechanism of action, dosing, and clinical presentations are comprehensively summarized. Each medication offers a distinct approach to manage ALS, aiming to alleviate the burdensome symptoms and slow the disease's progression, thereby improving the quality of life for individuals affected by this neurological condition. However, despite these advancements in pharmaceutical interventions, finding a definitive cure for ALS remains a significant challenge. Continuous investigation into ALS pathophysiology and therapeutic avenues remains imperative, necessitating further research collaborations and innovative approaches to unravel the complex mechanisms underlying this debilitating condition.

Development and Validation of a Liquid Chromatography-Tandem Mass Spectrometry Method for Analysis of Riluzole in Human Plasma and Its Application on a Bioequivalence Study

Introduction. As the first approved drug for amyotrophic lateral sclerosis (ALS) treatment, riluzole is known as a glutamatergic neurotransmission inhibitor administrated in 50 mg tablets twice daily. For this reason, a generic product of riluzole has been developed at a lower price by Hogar-Daroo, Iran, which would benefit patients.Aim. The objective of this study is to develop and validate a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the analysis of riluzole in human plasma samples and its application in the bioequivalence study of riluzole tablet.Materials and methods. The chromatography was performed by using a C18 column (100 mm, 4.6 mm, 5 mm), 0.1 % formic acid and acetonitrile (60 : 40, v/v) as the mobile phase, at a flow rate of 0.90 ml/min in the gradient program. Carbamazepine was used as an internal standard (IS). The method employed only 100 µL of human plasma for quantification by a liquid-liquid extraction technique. The multiple reaction monitoring modes (MRM) was used for quantification of ion transitions m/z 235.0/165.9 and m/z 137.6/110.0 for riluzole and the m/z 236.9/194.0 for the IS. Dwell time was set at 200 ms.Results and discussion. The calibration curve was linear over the concentration range 0.5–300 ng/mL. The lower limit of quantitation (LLOQ) was obtained at 0.5 ng/mL. The intra-day and inter-day accuracy ranged from 93.21 % to 101.34 % and 91.77 % to 104.88 % respectively. The intra-day and inter-day precision values ranged from 2.19 % to 5.69 % and 1.67 % to 5.31 % respectively, all within the FDA acceptable ±15 %.Conclusion. The validated method was applied in Iranian healthy subjects under fasting condition with a 50 mg riluzole tablet successfully.

Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis

The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. ClinicalTrials.gov Identifier: NCT03548311.

Emerging Drugs for Amyotrophic Lateral Sclerosis


 Horizon scan reports provide brief summaries of information regarding new and emerging health technologies. These technologies are identified through the CADTH Horizon Scanning Service as topics of potential interest to health care decision-makers in Canada. This Horizon Scan summarizes the available information regarding emerging drug therapies for the treatment of patients with amyotrophic lateral sclerosis.
 Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disorder characterized by muscle weakness and wasting. ALS can be classified as sporadic (sALS), which accounts for 85% to 90% of the cases, or familial (fALS), which includes 10% to 15% of the cases.
 At present, 2 drugs are available in Canada for the treatment of patients with ALS, riluzole and edaravone. These 2 drugs provide modest benefits in terms of survival and function.
 Many treatments are currently in various stages of clinical development. Fasudil, ibudilast, inosine, and masitinib are drugs of interest as they have completed phase II, and some have initiated phase III, of their respective clinical development. Several other drugs are in clinical development and are briefly described in this report: AT-1501, CNM-Au8, Engensis, Pridopidine, Verdiperstat, and Zilucoplan.
 Emerging drugs for ALS pertain to different drug classes. Despite different mechanisms of action, these drugs all aim at providing a neuroprotective effect that will result in slowing of disease progression, maintenance of patient functional status, and improvement in patient survival.
 Of the 4 ALS drugs of interest in late-stage development, Fasudil, Ibudilast, and Inosine have completed phase II of clinical development.
 The estimated completion date for phase III of clinical development for Masitinib is December 2022.

Industry reveals a suite of new drug structures

Tucked away at the end of the first week of the American Chemical Society Spring 2021 meeting was the always-anticipated “First-Time Disclosures” session, in which industry reveals the structures of its latest clinical drug candidates. The event is a rare opportunity for chemists to peek inside the medicinal chemistry industry’s process for designing and homing in on new drugs. Chemists from Bristol Myers Squibb, Janssen Research and Development, and Deciphera Pharmaceuticals presented new cancer drugs. In addition, Ivan Efremov of Fulcrum Therapeutics presented a candidate that targets sickle cell disease (shown); Grace Chuang of Cytokinetics discussed a treatment for the rare genetic heart disease, obstructive hypertrophic cardiomyopathy; and Michael Siu from Genentech spoke about a drug for amyotrophic lateral sclerosis, commonly known as ALS. Session organizer Nicole Goodwin of GlaxoSmithKline pointed out that pyrazoles were popular this year, appearing in three of the six candidate molecules. “Pyrazoles for the win,”

Riluzole ameliorates soluble Aβ1–42-induced impairments in spatial memory by modulating the glutamatergic/GABAergic balance in the dentate gyrus

Soluble amyloid beta (Aβ) is believed to contribute to cognitive deficits in the early stages of Alzheimer's disease (AD). Increased soluble Aβ1–42 in the hippocampus is closely correlated with spatial learning and memory deficits in AD. Riluzole (RLZ), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), has beneficial effects for AD. However, the mechanism underlying the effects remains unclear. In this study, its neuroprotective effect against soluble Aβ1–42-induced spatial cognitive deficits in rats was assessed. We found that intrahippocampal injection of soluble Aβ1–42 impaired spatial cognitive function and suppressed long-term potentiation (LTP) of the DG region, which was relevant to soluble Aβ1–42-induced shift of the hippocampal excitation/inhibition balance toward excitation. Interestingly, RLZ ameliorated Aβ1–42-induced behavioral and LTP impairments through rescuing the soluble Aβ1–42-induced excitation/inhibition imbalance. RLZ attenuated Aβ1–42-mediated facilitation of excitatory synaptic transmission by facilitating glutamate reuptake and decreasing presynaptic glutamate release. Meanwhile, RLZ attenuated the suppression of inhibitory synaptic transmission caused by Aβ1–42 by potentiating postsynaptic GABA receptor function. These results suggest that RLZ exerts a neuroprotective effect against soluble Aβ1–42-related spatial cognitive deficits through rescuing the excitation/inhibition imbalance, and it could be a potential therapy for AD.

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma.

Internal ribosome entry site (IRES)-mediated protein synthesis has been demonstrated to play an important role in resistance to mechanistic target of rapamycin (mTOR) targeted therapies. Previously, we have demonstrated that the IRES trans-acting factor (ITAF), hnRNP A1 is required to promote IRES activity and small molecule inhibitors which bind specifically to this ITAF and curtail IRES activity, leading to mTOR inhibitor sensitivity. Here we report the identification of riluzole (Rilutek®), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), via an in silico docking analysis of FDA-approved compounds, as an inhibitor of hnRNP A1. In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (GBM) affects with mTOR inhibitors in vitro and in GBM xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in glioblastoma.

Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study

BackgroundRiluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events.MethodsPatients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded.ResultsA total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment.ConclusionRiluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.

Non-Classical Synthons: Supramolecular Recognition by S⋅⋅⋅O Chalcogen Bonding in Molecular Complexes of Riluzole.

Classical examples of supramolecular recognition units or synthons are the ones formed by hydrogen bonds. Here, we report the ubiquity of a S⋅⋅⋅O chalcogen bonded synthon observed in a series of supramolecular complexes of the amyotrophic lateral sclerosis drug riluzole. Although the potential of higher chalcogens such as Se and Te to form robust and directional chalcogen bonded motifs is known, intermolecular sulfur chalcogen bonding is considered to be weak owing to the lower polarizability of S atoms. Here, the robustness and electronic nature of a S⋅⋅⋅O chalcogen bonding non-classical synthon, and the origin of its exceptional directionality have been explored. Bond orders of the drug-coformer chalcogen bonding are found to be as high as one third of a single bond, and they are largely ionic in nature. The contribution of the S⋅⋅⋅O chalcogen bonded motifs to the lattice energies of a series of crystals from the Cambridge Structural Database has been analyzed, showing they can be indeed significant, especially in molecules devoid of strong hydrogen bond donor groups.

Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs.

Over the past decades, a multitude of experimental drugs have been shown to delay disease progression in preclinical animal models of amyotrophic lateral sclerosis (ALS) but failed to show efficacy in human clinical trials or are still waiting for approval under Phase I-III trials. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Recently, an antioxidant drug, edaravone, developed by Mitsubishi Tanabe Pharma was found to be effective in halting ALS progression during early stages. The newly approved drug edaravone is a force multiplier for ALS treatment. This short report provides an overview of the two drugs that have been approved for ALS treatment and highlights an update on the timeline of drug development, how clinical trials were done, the outcome of these trials, primary endpoint, mechanism of actions, dosing information, administration, side effects, and storage procedures. Moreover, we also discussed the pressing issues and challenges of ALS clinical trials and drug developments as well as future outlook.

Long-term effects of edaravone on patients with amyotrophic lateral sclerosis

Background: One of free radical scavengers, edaravone, was approved in Japan as a therapeutic drug for amyotrophic lateral sclerosis (ALS) in 2015.

Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug

Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia.

Mitsubishi unit buys Israel’s NeuroDerm

Mitsubishi Tanabe Pharma, part of Mitsubishi Chemical Holdings, has agreed to buy the Israeli firm NeuroDerm for $1.1 billion. NeuroDerm develops drug-device pairings to treat central nervous system disorders. One of its candidates, ND0612, is undergoing Phase III trials for late-stage Parkinson’s, a point when treatment with oral levodopa no longer works. NeuroDerm’s approach is the continuous subcutaneous administration of levodopa via a small pump attached to the person’s belt. Mitsubishi Tanabe says the acquisition will help it raise U.S. sales to $715 million by 2020. Next month, the Japanese firm will launch its amyotrophic lateral sclerosis drug Radicava in the U.S.

(355) Riluzole actions on SK channels in the amygdala in acute arthritic and chronic neuropathic pain

Current therapeutic strategies for chronic pain are limited and often have variable efficacy and severe side effects. Complicating treatment further is the association of pain with negative affective states. The amygdala is a limbic structure that plays a key role in mediating emotional-affective aspects of pain. Here we tested effects of riluzole, a clinically available drug for amyotrophic lateral sclerosis, on acute and chronic pain behaviors. Evidence suggests that riluzole effects are mediated through a supraspinal site of action. Among riluzole actions is activation of small-conductance calcium-activated potassium (SK) channels, which have been reported to regulate neuronal firing in the central nucleus of the amygdala (CeA). We hypothesized that riluzole inhibits pain behaviors by activating SK channels in the CeA in rat models of acute arthritis pain (kaolin-carrageenan model) and chronic neuropathic pain (spinal nerve ligation [SNL] model). Supraspinally organized audible (nocifensive response) and ultrasonic (emotional-affective response) vocalizations, withdrawal thresholds, and anxiety-like behaviors on the elevated plus maze were measured in normal/sham controls, arthritic rats 5 h after induction, and neuropathic rats 4 weeks after SNL surgery. Arthritic and neuropathic rats showed increased vocalizations and anxiety-like behaviors and decreased withdrawal thresholds. Systemic (i.p.) riluzole administration in arthritic rats inhibited audible and ultrasonic vocalizations and anxiety-like behaviors with no effect on withdrawal thresholds, however in neuropathic rats, inhibitory riluzole effects were weaker and less consistent. Coapplication of systemic riluzole with stereotaxic (into CeA) apamin (selective SK channel blocker) blocked riluzole inhibition of vocalizations, but effects persisted with coapplication (into CeA) of a large-conductance calcium-activated potassium (BK) channel blocker (charybdotoxin) or offsite (into lateral-basolateral amygdala) coapplication of apamin. The data suggest that riluzole has beneficial effects on acute arthritis pain behaviors mediated at least in part by SK channels in the CeA, but benefits on chronic neuropathic pain behaviors are less prominent.

Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.

Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus, cornu ammonis 3 (CA3), and cornu ammonis 1 (CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1, the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.

Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1δ inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood–brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.

Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS

The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid α-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1 activating compounds may be used therapeutically to treat diseases related to BBB dysfunction.

Zebrafish Make It to Hollywood!

ZebrafishVol. 9, No. 3 NewsZebrafish Make It to Hollywood!Chloé Drapeau and Pierre DrapeauChloé DrapeauCollege Notre-Dame High School, Montreal, Canada.Search for more papers by this author and Pierre DrapeauUniversity of Montreal, Montreal, Canada.Search for more papers by this authorPublished Online:17 Sep 2012https://doi.org/10.1089/zeb.2012.9996AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Zebrafish Make It to Hollywood!." , 9(3), p. 149FiguresReferencesRelatedDetailsCited BySimple animal models for amyotrophic lateral sclerosis drug discovery13 June 2016 | Expert Opinion on Drug Discovery, Vol. 11, No. 8 Volume 9Issue 3Sep 2012 InformationCopyright 2012, Mary Ann Liebert, Inc.To cite this article:Chloé Drapeau and Pierre Drapeau.Zebrafish Make It to Hollywood!.Zebrafish.Sep 2012.149-149.http://doi.org/10.1089/zeb.2012.9996Published in Volume: 9 Issue 3: September 17, 2012PDF download

Emerging drugs for amyotrophic lateral sclerosis

Introduction:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that results in increasing disability and that is uniformly fatal. Since its approval in the 1990s, riluzole remains the sole treatment for ALS offering modest survival benefit. While significant advances have been made in the symptomatic management of the disease, more effective drug therapy targeting disease progression is sorely needed.Areas covered:Advances in the understanding of pathogenic mechanisms involved in disease development and progression have provided multiple avenues for developing effective treatment strategies. This review highlights recent discoveries relating to these diverse mechanisms and their implications for the development of drug therapy. Previous human clinical trials that have targeted these pathways are mentioned and ongoing drug trials are discussed.Expert opinion:The search for effective drug therapy faces important challenges in the areas of basic science and animal research, translation of these results into human clinical trials, inherent bias in human studies and issues related to delays in clinical diagnosis. How these issues may be addressed and why ALS research constitutes fertile grounds for drug development not only for this devastating disease, but also for other more prevalent neurodegenerative diseases, is discussed in this review.

The need for biomarkers in amyotrophic lateral sclerosis drug development

Recent contributions to Neurology ® have highlighted the disappointing lack of demonstrated efficacy of novel therapeutic approaches to amyotrophic lateral sclerosis (ALS).1–3 Failure of translation, from promising preclinical studies to positive clinical trials, has raised concerns about the relevance of animal models and about clinical trial design. Development of novel therapeutics in ALS is also severely hampered by the lack of a biologic marker (biomarker) defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to a therapeutic intervention.”4 The importance of biomarkers in therapy development is underscored by the fact that for diseases in which good biomarkers exist, such as glycosylated hemoglobin for diabetes and serum lipid profiles for atherosclerotic coronary artery disease, there are multiple approved drugs, while for diseases in which there are no good biomarkers, such as Alzheimer disease, muscular dystrophy, and ALS, there are very few therapeutic options. Biomarkers have been proposed for ALS, although none are currently incorporated into clinical …