More recently, the second-generation MAO-B inhibitor rasagiline also showed no beneficial effects on survival and disease progression in two studies54,55. succumbed to the disease aged 37. Today, almost 80 years later, ALS remains almost as intractable as it was back then. Scores of clinical trials have only yielded two interventional treatments: Riluzole, approved in 1995, and edaravone, approved by the FDA in 2017 (Table 1). In this review we summarize the state of play of interventional drugs currently or formerly in the medical center for the treatment of ALS. We also spotlight exciting novel therapeutic avenues built on our rapidly expanding understanding of the pathogenesis of this devastating disease. Table 1 Overview of disease-modifying therapies in clinical trials Anti-inflammatory/immune-modulatoryModalityDrug nameMechanism of actionPhase/OutcomePrimary endpointReferencesAntibodyTocilizumabAntibody targeting IL-6RPh 2Safety, tolerability92,93PolypeptideACTH/Acthar gelACTH C stimulates release of glucocorticoidsPh 2 haltedALSFRS-R258,259PolypeptideIL-2Promotes differentiation of regulatory T cellsPh 2Time to death [18 m]91SMIbudilastPDE inhibitor; suppresses pro-inflammatory microglial activationPh 2Safety, tolerability73SMPentoxifyllinePDE inhibitorPh 3 failureTime to death [18 m]74SMMasitinibCSF-1R/c-kit inhibitor; suppresses microglial activation and proliferationPh 2/3ALSFRS-R83C86SMNP001Stabilized form of sodium chlorite; downregulates NFkB expression and IL-1 productionPh 2 failureALSFRS-R69,70SMThalidomideSuppresses production of TNF-Ph 2 failureCo-primary ALSFRS-R + PFT75Peptide mimeticGlatiramer AcetateMBP decoy; modulates T cell reactivityPh 2 failureALSFRS-R90SMCC100Caffeic acid phenetyl ester; suppresses NF-kB and MAPK signalingPh 1Safety, tolerability71SMFingolimodS1PR1 agonist; reduces circulating lymphocytesPh 2ALSFRS-R + SVC87SMMinocyclineSuppresses pro-inflammatory microglial activationPh 3 failureALSFRS-R68SMPioglitazonePPAR- agonist; suppresses NF-B signalingPh 2 failureOverall survival67SMDNL747RIPK1 inhibitor; suppresses pro-inflammatory microglial cytokine productionPh 1Safety, tolerability79SMFasudilROCK inhibitor; suppresses pro-inflammatory microglial cytokine productionPh 2ASecurity, tolerability72SMOno-2506Arundic acid; modulates astrocyte activityPh 2 failureSVC76ProteinAnakinraIL-1 receptor antagonistPh 1Safety, tolerability94NanobubblesRNS60Suppresses microglial NFkBPh 2ALSFRS-R78Anti-excitatorySMRiluzoleReduces glutamatergic neuro-transmission; Na+ channel blockerApprovedTracheostomy-free survival16C18SMRetigabineK+ channel agonistPh 2SICI30, 260SMMemantineNMDA receptor antagonistPh 2 failureALSFRS-R25SMTalampanelAMPA receptor antagonistPh 2 failureIsometric arm strength27SMPerampanelAMPA receptor antagonistPh 2ALSFRS-R28,29SMMexiletineNa+ channel blockerPh 2 failureALSFRS-R31,32SMCeftriaxoneIncreases astrocytic EEAT2Ph 3 failureCo-primary survival + ALSFRS-R22SMCelecoxibCOX2 inhibitor; suppresses astrocytic glutamate releasePh 2 failureMVIC23SMLamotrigineNa+ channel blockerPh 2 failureNorris level261SMNimodipineCa++ channel blockerPh 2 failureFVC12SMGabapentinBlocks glutamate synthesis; Ca++ channel blockerPh 3 failureArm muscle mass strength34AntioxidantsSMEdaravoneFree radical scavengerApprovedALSFRS-R35SMEpi-589Modulates levels of glutathionePh 2SafetyN/ASMN-AcetylcysteineRadical oxygen scavenger (glutathione precursor)Ph 2 failureSurvival*49VitaminVitamine ERadical oxygen scavengerPh 2 failureNorris limb score; Survival*46,47SMCoenzyme Q10Radical oxygen scavenger; cofactor in mitochondrial electron transport chainPh 2 failureALSFRS-R48SMSelegilineMAO-B inhibitor; upregulates SOD, catalase activityPh 2 failureAALSRS53SMRasagilineMAO-B inhibitorPh 2 failureTime to death; ALSFRS-R54,55SOD1-targetingSMCu(II)-ATSMTargets misfolded SOD1Ph 1/2Safety, tolerability100ASOBIIB067Reduces levels of mutant SOD1Ph 1Safety, Mouse monoclonal to ERBB3 tolerability110,111SMPyrimethamineReduces levels of SOD1Ph 1/2Change in CSF SOD1109Troponin bindersSMLevosimendanMuscle Troponin activatorPh 3Supine SVC99,100SMTirasemtivFast skeletal muscle mass troponin activatorPh 3 failureSVC31,97SMCK-2127107Fast skeletal muscle mass troponin activatorPh 2SVC98(Neuro)trophic factorsPolypeptideIGF-1Recombinant Procaine human IGF-1Ph 3 mixed/failureAALSRS; MMT score130,131,133SMXaliproden5-HT1A agonist; Procaine non-peptide neurotrophic factor enhancerPh 3 failureSurvival*, time to VC 50%139PolypeptideEPORecombinant human erythropoietinPh 3 failureSurvival*136PolypeptideBDNFRecombinant human BDNFPh 3 failureFVC, 9-month survival135PeptideGM604Peptide fragment of motoneurotrophic factorPh 2ASecurity, tolerability, biomarkers137PolypeptideCNTFRecombinant human CNTFPh 2/3 failureIsometric muscle mass strength; MVIC+FCV132,134PlasmidSB509ZFP transcription factor for expression of VEFGPh 2ALSFRS-R140PlasmidVM202Expression of HGFPh 1/2Safety, tolerability142PlasmidsNN0029Expression of VEGF165Ph 1/2Safety, tolerability141PolypeptideKP-100Recombinant human HGFPh 1Safety, tolerability138Modulators of mitochondrial functionSMDexpramipexoleInhibits mitochondrial permeability transition porePh 3 failureCAFS145SMOlexosimeInhibits mitochondrial permeability transition porePh 2/3 failure18-month survival146SMCreatineIncreases mitochondrial ATP productionPh 2 failureSurvival*; MVIC147C150SMAcetyl-L-carnitineTransports long-chain fatty acids across mitochondrial membranePh 2Loss of self-sufficiency151Autophagy inducersSMLithiumInhibits inositol monophosphatasePh 3 failure18-month survival120,121SMRapamycinmTOR inhibitorPh 2Treg number122SMTamoxifenIncreases Beclin-1Ph 2Arm strength127Other therapeutic approachesAntibodyOzanezumabTargets NOGO-APh 2 failureJoint rank score ALSRFS-R + 48wk survival262SMGDC-0134DLK inhibitor; suppresses JNK-dependent stress responsePh 1Safety, tolerability263N/AYAM80N/APh 2Safety, ALSFRS-R264VitaminMethylcobalaminActive vitamin B12; decreases levels of homocysteinePh 2/3 failureSurvival* + ALSFRS-R265SMPimozideT-type calcium channel blocker; strengthens NMJsPh 2ALSFRS-R266SMOmigapil/TCH346Anti-apoptotic; binds GAPDHPh 2/3 failureALSFRS-R267SMDeferiproneIron metal chelatorPh 2, 3CAFS268SMAMX0035Upregulation of warmth shock proteinsPh Procaine 2Safety, tolerability, ALSFRS-R269,270SMArimoclomolInduces.